Omega-3 fatty acid ester compositions

ABSTRACT

Compositions including at least one Omega-3 fatty acid ester and at least one surface active agent are provided; wherein the compositions form micelles when in contact with an aqueous medium. Also provided is a method of administering to a subject such a composition, wherein the at least one Omega-3 fatty acid ester forms micelles when in contact with an aqueous medium, and the bioavailability of the at least one Omega-3 fatty acid ester is substantially independent of a food effect. The compositions are useful for treating cardiovascular conditions or disorders in a subject and for reducing side effects associated with the ingestion of Omega-3 fatty acid esters. Further provided are also various dosage forms for administering the compositions and use of the compositions in functional foods. Provided herein are also kits with instructions on how to administer the compositions.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation-in-Part application and claims thebenefit of priority from U.S. patent application Ser. No. 14/578,697filed Dec. 22, 2014 which is a Continuation-in-Part application andclaims the benefit of priority from U.S. patent application Ser. Nos.14/456,731 and 14/456,750 both filed Aug. 11, 2014 which areContinuation applications and claim the benefit of priority fromInternational Patent Application No. PCT US2013/030211 filed Mar. 11,2013 which in turn claims the benefit of priority from U.S. ProvisionalPatent Application No. 61/618,161 filed Mar. 30, 2012.

BACKGROUND

According to the World Health Organization's (WHO) fact sheet onCardiovascular Diseases (CVDs), CVDs are the number one cause of deathglobally. (Fact Sheet No. 317, September 2012 accessed atwww.who.int/mediacentre/factsheets/fs317/en/index.html on Jan. 31, 2013.The WHO estimates that an estimated 17.3 million people died from CVDsin 2008, representing 30% of all global deaths. Of these deaths, anestimated 7.3 million were due to coronary heart disease (CHD) and 6.2million were due to stroke. The WHO also estimates that by 2030, almost25 million people will die from CVDs, mainly from heart disease andstroke. The Global Burden of Disease Study estimates that the developingcountries contributed 3.5 million of the 6.2 million global deaths fromCHD in 1990. (Murray C J L and Lopez A D. The Global Burden of Disease AComprehensive Assessment of Mortality and Disability from Disease,Injuries and Risk Factors in 1990 and Projected to 2020. Boston, MaHarvard University Press; 1996). The projections estimate that thesecountries will account for 7.8 million of the 11.1 million deaths due toCHD in 2020. The developed countries are not immune to CHD. For example,in the USA and Europe, CHD remains the largest single cause of death anddisability. In 2005, CHD caused approximately 1 of every 5 deaths in theUSA. (Heron M P, et. al. Deaths preliminary data for 2006. Natl. Vital.Stat. Rep. 2008; 56:1-52.) According to the Centers for Disease Controland Prevention it is the leading cause of death in America.Approximately 37% of people who develop a coronary event in a given yearwill die from it. While major reductions in CVD related mortality havebeen achieved in Europe, CVD still accounts for 54% of all deaths inwomen and 43% of all deaths in men.

CVD is associated with many risk factors. Of these risk factors,hyperlipidemia (e.g., hypertriglyceridemia) and hypercholesterolemia aresignificant indicators of CVD. As such, dietary supplements,nutraceuticals, and prescribed drugs containing Omega-3 fatty acidesters, such as the ethyl esters of EPA and DHA, are currently used forthe treatment of CVD and, in particular, for the reduction of elevatedtriglycerides.

However, administration of dietary supplements, nutraceuticals, andprescribed drugs containing Omega-3 fatty acid esters presentssignificant challenges. For example, current dietary supplements,nutraceuticals, and prescribed drugs containing Omega-3 fatty acidesters have variable absorption and efficacy when orally administered.In particular, current compositions have a pronounced “food effect,”with poor absorption when taken while fasting or with a low fat meal.When taken with fatty foods, the absorption of Omega-3 fatty acid estersimproves, due in part to the presence of bile salts that are released inthe intestines, which aid absorption of Omega-3 fatty acid esters.

To overcome low absorption, patients can be dosed with compositionshaving greater amounts of Omega-3 fatty acid esters, but there arepractical limitations to this approach due to the side effects that arecommonly associated with such compositions. The oxidative degradation ofOmega-3 fatty acid esters that occurs over time can result in anunpleasant aftertaste following administration, especially when consumedin large quantities. Burping and stomach upset are further unpleasantside effects associated with the consumption of Omega-3 fatty acidesters. Following consumption, Omega-3 fatty acid esters tend to floaton top of liquid contents in the stomach, forming a layer that preventsthe passage of small gas bubbles. When sufficient gas has built up toovercome the surface tension of the oil layer, a person burps. The burpsusually contain a fishy taste and smell.

Accordingly, side effects associated with the administration of currentcompositions comprising Omega-3 fatty acid esters (e.g., susceptibilityto the food effect, large doses to attain efficacy, and the resultingaftertaste, unpleasant smell, and burping) are known to significantlyreduce patient compliance.

While practicing a healthy lifestyle may reduce the incidence of CVD,new therapeutic approaches to manage CVD are warranted. These newapproaches might include the discovery of new drugs or improve uponcurrent medications used to treat CVD. The discovery of new drugs,however, comes at a high price with no certainty of eventual success.Accordingly, new or more efficient ways of delivering currentmedications with a proven safety and efficacy profile should bedeveloped. Thus, there is a need for improved compositions comprisingOmega-3 fatty acid esters, such as the ethyl esters of EPA and DHA, thatare less susceptible to food effect and which attain high efficacy atlower doses. Ideally, such improved compositions would minimize oreliminate an unpleasant smell and/or an unpleasant aftertaste, and/orburping in the patient. Such an improved composition with reduced sideeffects would improve patient compliance and more effectively treat therisk factors related to cardiovascular disease.

SUMMARY

In all of the embodiments provided herein, all of the compositions arefree of Omega-3 free fatty acids. Provided herein, in certainembodiments, are compositions comprising EPA and DHA esters incombination with at least one surface active agent. In certainembodiments, the ratio of EPA ester to DHA ester is from more than 2:1to not more than 3.4:1. Certain embodiments provide for the ratio of theEPA ester to the DHA ester to be from about 2:1 to about 3.4:1. Providedherein, in certain embodiments, are compositions comprising at least oneOmega-3 fatty acid ester and at least one surface active agent. Incertain embodiments, the Omega-3 fatty acid ester is selected from thegroup consisting of hexadecatrienoic acid, α-linolenic acid, stearidonicacid, eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoicacid, docosapentenoic acid, docosahexaenoic acid, tetracosapentenoicacid, tetracosahexaenoic acid, or combinations thereof. Certainembodiments provide for compositions comprising the ethyl esterderivative of said Omega-3 fatty acid ester, optionally in combinationwith at least one surface active agent, at least one terpene, at leastone antioxidant, or combinations thereof. Certain embodiments alsoprovide for combinations of different Omega-3 fatty acid esters inratios of from about 2:1 to about 3.4:1. Other embodiments call for theratio to be more than 2:1 to not more than 3.4:1. Typically, the ratiois about 2.4:1. Certain embodiments provide a method for treating avariety of conditions or disorders that can be treated by administeringsaid Omega-3 fatty acid esters in compositions described hereincomprising the described ratios, optionally with at least one surfaceactive agent, at least one terpene, at least one antioxidant, orcombinations thereof. The compositions described herein minimize severalside effects found in currently marketed compositions containing Omega-3fatty acid esters that can deter a human subject from complying withdosing regimen necessary to treat a condition or disorder treatable byadministration of Omega-3 fatty acid esters. In certain embodiments, thebioavailability of said Omega-3 fatty acid esters when administered ascertain compositions described herein is substantially the same whenadministered with or without food, i.e., substantially independent offood effect, to a human subject in need of such administration.

Thus, certain embodiments call for pharmaceutical compositionscomprising at least one Omega-3 fatty acid ester and at least onesurface active agent; wherein said at least one Omega-3 fatty acid estercomprises at least about 40% (wt/wt) of the composition.

Certain embodiments call for pharmaceutical compositions comprising afirst Omega-3 fatty acid ester selected from the group consisting ofhexadecatrienoic acid, α-linolenic acid, stearidonic acid,eicosatrienoic acid, eicosapentaenoic acid, heneicosapentaenoic acid,docosapentenoic acid, docosahexaenoic acid, tetracosapentenoic acid,tetracosahexaenoic acid, and a second Omega-3 fatty acid ester selectedfrom the group consisting of hexadecatrienoic acid, α-linolenic acid,stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid,heneicosapentaenoic acid, docosapentenoic acid, docosahexaenoic acid,tetracosapentenoic acid, tetracosahexaenoic, such that the first andsecond Omega-3 fatty acid esters selected are different from each otherand the ratio of the first and second Omega-3 fatty acid esters are in aratio of more than 2:1 to not more than 3.4:1 (first Omega-3 fatty acidester:second Omega-3 fatty acid ester); wherein the first and secondOmega-3 fatty acid esters combined comprise at least about 40% (wt/wt)of the composition and wherein said composition is substantially free ofactive ingredients other than said Omega-3 fatty acid esters.

Certain embodiments call for the use of at least one Omega-3 fatty acidester. Typically, the Omega-3 fatty acid ester is an ethyl ester.

Certain embodiments call for pharmaceutical compositions comprising atleast one Omega-3 fatty acid ester and at least one terpene; whereinsaid at least one Omega-3 fatty acid ester comprises at least about 40%(wt/wt) of the composition and is substantially free of activeingredients other than Omega-3 fatty acid esters. In certainembodiments, the at least one Omega-3 fatty acid ester comprises about40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%. The terpene is typically, butnot necessarily d-limonene. In certain other embodiments, suchcompositions comprise natural orange-oil.

Certain embodiments provide for compositions comprising EPA ethyl estersand DHA ethyl esters and at least one terpene, wherein the ratio ofEPA:DHA is about 2.4:1 and wherein said EPA and DHA ethyl esterscombined comprise from about 40% (wt/wt) to about 95% (wt/wt) of saidcomposition. In certain embodiments, the EPA and DHA ethyl esterscombined comprise about 40% (wt/wt) of said composition. The terpene istypically, but not necessarily d-limonene. In certain other embodiments,such compositions comprise natural orange-oil.

In embodiments comprising substantially pure d-limonene, the d-limoneneis from about 95% to about 98% pure. In certain embodiments, thesubstantially pure d-limonene is at least 95%, 96%, 97% or 98% pure.

In certain embodiments, the Omega-3 fatty acid ester is selected fromthe group consisting of at least one EPA ester, at least one DHA esteror combinations thereof, and comprises at least one surface activeagent. In certain embodiments, the at least one EPA ester and at leastone DHA ester is substantially pure. Certain embodiments also providefor compositions comprising at least one EPA ester and at least one DHAester in ratios from about 2:1 to about 3.4:1, which are substantiallyfree of active ingredients other than Omega-3 fatty acid esters.Compositions comprising other ratios are also described. Certaincompositions can also be free of natural orange oil or d-limonene. Incertain embodiments, the Omega-3 fatty acid esters comprise at least 40%of the composition. Typically, the Omega-3 EPA and DHA esters are ethylesters. Certain compositions described herein form micelles in anaqueous medium and are free of food effect. Certain compositions, whenadministered with or without food, are substantially free of foodeffect. Provided herein are also methods for treating cardiovascularconditions or disorders using the compositions described. Thecompositions described herein minimize or eliminate side effects whencompared to the administration of prior art compositions. Also providedare packaged compositions or kits of the Omega-3 fatty acid esterscomprising one or more unit dosage forms together with instructions onusing the compositions.

Accordingly, in at least one embodiment is provided, a pharmaceuticalcomposition comprising at least one EPA ester and at least one DHA esterin a weight to weight ratio of more than about 2:1 to not more thanabout 3.4:1 (EPA:DHA) and at least one surface active agent, whereinsaid EPA and DHA esters combined comprises from about 40% to about 85%by weight of the composition. In certain such embodiments, the EPA andDHA ethyl esters combined comprise about 50% (wt/wt) of saidcomposition.

In at least one other embodiment is provided, a pharmaceuticalcomposition comprising at least one EPA ester and at least one DHA esterin a weight to weight ratio from about 2:1 to about 3.4:1 (EPA:DHA) andat least one surface active agent, wherein said EPA and DHA esterscombined comprises from about 40% to about 85% by weight of thecomposition. In certain such embodiments, the EPA and DHA ethyl esterscombined comprise about 50% (wt/wt) of said composition.

In at least one other embodiment is provided, a pharmaceuticalcomposition comprising at least one EPA ester and at least one DHA esterin a weight to weight ratio of more than 2:1 to not more than 3.4:1(EPA:DHA) and at least one surface active agent, wherein said EPA andDHA esters combined comprises from about 40% to about 85% by weight ofthe composition. In certain such embodiments, the EPA and DHA ethylesters combined comprise about 50% (wt/wt) of said composition.

In at least one other embodiment is provided, a pharmaceuticalcomposition comprising at least one EPA ester and at least one DHA esterin a weight to weight ratio of more than 2:1 to not more than 3.4:1(EPA:DHA) and at least one surface active agent, wherein said EPA andDHA esters combined comprises from about 40% to about 85% by weight ofthe composition, and wherein the composition when administered with orwithout food to a human subject in need of such administration issubstantially independent of food effect. In certain such embodiments,the EPA and DHA ethyl esters combined comprise about 50% (wt/wt) of saidcomposition.

In at least one embodiment, the compositions described herein comprisesubstantially pure at least one EPA ester and/or at least one DHA ester.

In at least one embodiment, the compositions described herein consistessentially of the at least one EPA ester and/or the at least one DHAester.

In certain embodiments, either of, or each of, the EPA and DHA estercomprising the composition is the ethyl ester.

In certain embodiments, the compositions described herein comprisesubstantially pure EPA ethyl ester and/or substantially pure DHA ethylester.

In certain embodiments, the compositions described herein consistessentially of substantially pure EPA ethyl ester and/or substantiallypure DHA ethyl ester.

In certain embodiments, the ratio of the EPA and DHA ester comprisingthe composition is about 2.4:1 (EPA ester:DHA ester).

Certain embodiments call for compositions comprising either naturalorange oil from about 0.1% to about 5% (wt/wt) of said composition. Inembodiments comprising natural orange oil the natural orange oil ispresent at about 1.6% (wt/wt) of the composition. Certain otherembodiments comprise substantially pure d-limonene from about 0.1% toabout 5%. In embodiments comprising substantially pure d-limonene, thed-limonene is present at about 1.5% (wt/wt) of the composition.

In certain embodiments, the pharmacologic effect of the compositionsdescribed herein is substantially independent of a food effect uponadministration to a subject.

In certain embodiments, the compositions of the invention are doseproportional. Accordingly, in certain embodiments the baseline adjustedAUC_(0-t) is dose adjusted proportionally for EPA and DHA total lipidsselected from the group consisting of a 2.0 g dose, 2.5 g dose, 3.0 gdose, 3.5 g dose, 4.0 g dose, 4.5 g dose, 5.0 g dose and 5.5 g dose. Incertain embodiments dose of the compositions of the invention describedherein are adjusted proportionally for EPA and DHA total lipids selectedfrom the group consisting of a 2.0 g dose, 2.5 g dose, 3.0 g dose, 3.5 gdose, 4.0 g dose, 4.5 g dose, 5.0 g dose and 5.5 g dose compared toequivalent doses for LOVASA® or EPANOVA®.

In at least one embodiment, the composition of the invention whenadministered after a single 6 g dose (2,172 mg of EPA+996 mg of DHA) toa human under fed and fasted conditions at equal dosage strengthsprovides for a baseline adjusted AUC_(0-t) arithmetic mean under fedconditions for EPA total lipids and DHA total lipids from about 1495nmol·hr/ml to about 3569 nmol·hr/ml and from about 530 nmol·hr/ml toabout 1486 nmol·hr respectively; and a baseline adjusted AUC_(0-t)arithmetic mean under fasting conditions for EPA total lipids and DHAtotal lipids from about 1169 nmol·hr/ml to about 3239 nmol·hr/ml andfrom about 647 nmol·hr/ml to about 1615.7 nmol·hr/ml respectively. Incertain embodiments, the baseline adjusted AUC_(0-t) arithmetic meanunder fed conditions for EPA total lipids and DHA total lipids is about2532 nmol·hr/ml and about 1008 nmol·hr/ml respectively; and a baselineadjusted AUC_(0-t) arithmetic mean under fasting conditions for EPAtotal lipids and DHA total lipids is about 2204 nmol·hr/ml and about1131 nmol·hr/ml respectively.

In at least one embodiment, the composition of the invention whenadministered after a single 6 g dose (2,172 mg of EPA+996 mg of DHA) toa human under fed and fasted conditions at equal dosage strengthsprovides for a baseline adjusted T_(max), arithmetic mean under fedconditions for the EPA total lipids and DHA total lipids from about 5.3to about 6.4 hours and from about 4.5 to about 6.4 hours respectively;and the baseline adjusted T_(max), arithmetic mean under fastingconditions for the EPA total lipids and DHA total lipids from about 3.8to about 6.7 hours and from about 4.0 to about 7 hours respectively. Incertain embodiments, the baseline adjusted T_(max), arithmetic meanunder fed conditions for the EPA total lipids and for DHA total lipidsis about 6 hours and about 5.4 hours respectively, and the baselineadjusted T_(max), arithmetic mean under fasting conditions for the EPAtotal lipids and DHA total lipids is about 5.2 and about 5.5 hoursrespectively.

In at least one embodiment, the composition of the invention whenadministered after a single 6 g dose (2,172 mg of EPA+996 mg of DHA) toa human under fed and fasted conditions at equal dosage strengthsprovides for a baseline adjusted C_(max) arithmetic mean under fedconditions for the EPA total lipids and DHA total lipids from about 172to about 454 nmol/ml and from about 97 to about 197 nmol/mlrespectively; and the baseline adjusted C_(max) arithmetic mean underfasting conditions for the EPA total lipids and DHA total lipids fromabout 115.5 to about 313 nmol/ml and from about 66 to about 169 nmol/mlrespectively. In certain embodiments, the baseline adjusted C_(max)arithmetic mean under fed conditions for the EPA total lipids and DHAtotal lipids is about 313 nmol/ml and about 147 nmol/ml respectively;and the baseline adjusted C_(max) arithmetic mean under fastingconditions for the EPA total lipids and DHA total lipids is about 214nmol/ml and about 117 nmol/ml respectively.

In at least one embodiment, the composition of the invention whenadministered after a single 6 g dose (2,172 mg of EPA+996 mg of DHA) toa human under fed and fasted conditions at equal dosage strengthsprovides for a baseline adjusted AUC_(0-t) arithmetic mean under fedconditions for EPA free fatty acids and DHA free fatty acids from about7 μg·hr/ml to about 14.5 μg·hr/ml and from about 1.1 μg·hr/ml to about8.7 μg·hr/ml respectively; and a baseline adjusted AUC_(0-t) arithmeticmean under fasting conditions for EPA free fatty acids and DHA freefatty acids from about 4.3 μg·hr/ml to about 8.5 μg·hr/ml and from 0μg·hr/ml to about 3.5 μg·hr/ml respectively. In certain embodiments, thebaseline adjusted AUC_(0-t) arithmetic mean under fed conditions for EPAfree fatty acids and DHA free fatty acids is about 10.82 μg·hr/ml andabout 5 μg·hr/ml respectively; and a baseline adjusted AUC_(0-t)arithmetic mean under fasting conditions for EPA free fatty acids andDHA free fatty acids is about 6.3 μg·hr/ml and about 1.65 μg·hr/mlrespectively.

In at least one embodiment, the composition of the invention whenadministered after a single 6 g dose (2,172 mg of EPA+996 mg of DHA) toa human under fed and fasted conditions at equal dosage strengthsprovides for a baseline adjusted T_(max), arithmetic mean under fedconditions for the EPA free fatty acids and DHA free fatty acids fromabout 4.65 to about 6.4 hours and from about 2 to about 10 hoursrespectively; and the baseline adjusted T_(max), arithmetic mean underfasting conditions for the EPA free fatty acids and DHA free fatty acidsfrom about 3.7 to about 5.2 hours and from about 3.7 to about 4.5 hoursrespectively. In certain embodiments, the baseline adjusted T_(max),arithmetic mean under fed conditions for the EPA free fatty acids andfor DHA free fatty acids is about 5.5 hours and about 5.9 hoursrespectively, and the baseline adjusted T_(max), arithmetic mean underfasting conditions for the EPA free fatty acids and DHA free fatty acidsis about 4.4 and about 4.1 hours respectively.

In at least one embodiment, the composition of the invention whenadministered after a single 6 g dose (2,172 mg of EPA+996 mg of DHA) toa human under fed and fasted conditions at equal dosage strengthsprovides for a baseline adjusted C_(max) arithmetic mean under fedconditions for the EPA free fatty acids and DHA free fatty acids fromabout 0.8 to about 1.83 μg/ml and from about 0.6 to about 2 μg/mlrespectively; and the baseline adjusted C_(max) arithmetic mean underfasting conditions for the EPA free fatty acids and DHA free fatty acidsfrom about 0.51 to about 1.8 μg/ml and from about 0.5 to about 2.2 μg/mlrespectively. In certain embodiments, the baseline adjusted C_(max)arithmetic mean under fed conditions for the EPA free fatty acids andDHA free fatty acids is about 1.32 μg/ml and about 1.3 μg/mlrespectively; and the baseline adjusted C_(max) arithmetic mean underfasting conditions for the EPA free fatty acids and DHA free fatty acidsis about 1 μg/ml and about 1.4 μg/ml respectively.

In at least one embodiment, the composition of the invention whenadministered after a single 6 g dose (2,172 mg of EPA+996 mg of DHA) toa human under fed conditions at equal dosage strengths provides for aAUC_(0-t) arithmetic mean under fed conditions for the EPA ethyl esterand DHA ethyl ester from 0 to about 0.91 μg·/ml and from about 0.6 toabout 1.5 μg·/ml respectively. In certain embodiments, the baselineadjusted AUC_(0-t) arithmetic mean under fed conditions for EPA ethylester and DHA ethyl ester is about 0.4 μg·hr/ml and about 0.83 μg·hr/mlrespectively

In at least one embodiment, the composition of the invention whenadministered after a single 6 g dose (2,172 mg of EPA+996 mg of DHA) toa human under fed conditions at equal dosage strengths provides for abaseline adjusted C_(max) arithmetic mean under fed conditions for theEPA ethyl ester and DHA ethyl ester from about 0 to about 0.48 μg/ml andfrom about 0.03 to about 0.59 μg/ml respectively. In certainembodiments, the baseline adjusted C_(max) arithmetic mean under fedconditions for the EPA ethyl ester and DHA ethyl ester is about 0.18μg/ml and about 0.31 μg/ml respectively.

In at least one embodiment, the composition of the invention whenadministered after a single 6 g dose (2,172 mg of EPA+996 mg of DHA) toa human under fed conditions at equal dosage strengths provides for abaseline adjusted T_(max), arithmetic mean under fed conditions for theEPA ethyl ester and DHA ethyl ester from about 1.75 hr to about 5 hr andfrom about 2.3 hr to about 3.83 hr respectively. In certain embodiments,the baseline adjusted T_(max), arithmetic mean under fed conditions forthe EPA ethyl ester and for DHA ethyl ester is about 3.34 hours andabout 3.1 hours respectively.

In certain embodiments, the baseline adjusted AUC_(0-t) is dose adjustedproportionally for EPA and DHA total lipids selected from the groupconsisting of a 2.0 g dose, 2.5 g dose, 3.0 g dose, 3.5 g dose, 4.0 gdose, 4.5 g dose, 5.0 g dose and 5.5 g dose.

In at least one embodiment, a pharmaceutical mixed-fatty-acidscomposition in which, a) at least 80% by weight of the composition iscomprised of a combination of (all-Zomega-3)-5,8,11,14,17-eicosapentaenoic acids (EPA) and (all-Zomega-3)-4,7,10,13,16,19-docosahexaenoic acids (DHA) in a weight ratioof EPA:DHA of from about 1:2 to about 2:1; b) (all-Zomega-3)-6,9,12,15,18-heneicosapentaenoic acid is present in an amountof at least one percent by weight; and c) at least one surface activeagent is provided. These compositions can optionally further comprisenatural orange oil from about 0.1% to about 5% (wt/wt) or substantiallypure d-limonene from about 0.1% to about 5% (wt/wt) of the composition.The natural orange oil is typically present at about 1.6% (wt/wt) ofsaid composition and d-limonene is typically present at about 1.5%(wt/wt) of the composition.

In at least one embodiment, a mixed-fatty-acids composition for thetreatment or prophylaxis of at least one of the multiple risk factorsfor CVD in which, a) at least 80% by weight of the composition iscomprised of Omega-3 fatty acids; b) at least 80% by weight of the totalfatty acid content of the composition is comprised of a combination of(all-Z omega-3)-5,8,11,14,17-eicosapentaenoic acid (EPA) and (all-Zomega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio ofEPA:DHA of from 1:2 to 2:1, c) Omega-3 fatty acids other than EPA andDHA are present in an amount of at least 1.5% by weight of the totalfatty acids; and c) at least one surface active agent is provided. Thesecompositions can optionally further comprise natural orange oil fromabout 0.1% to about 5% (wt/wt) or substantially pure d-limonene fromabout 0.1% to about 5% (wt/wt) of the composition. The natural orangeoil is typically present at about 1.6% (wt/wt) of said composition andd-limonene is typically present at about 1.5% (wt/wt) of thecomposition.

In at least one embodiment a pharmaceutical mixed-fatty-acidscomposition in which, a) at least 80% by weight of the composition iscomprised of a combination of (all-Zomega-3)-5,8,11,14,17-eicosapentaenoic acid (EPA) and (all-Zomega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio ofEPA:DHA of from 1:2 to 2:1, b) at least 3% by weight of the compositionis comprised of Omega-3 fatty acids other than EPA and DHA that have 18,20, 21, or 22 carbon atoms, and c) at least one surface active agent isprovided. These compositions can optionally further comprise naturalorange oil from about 0.1% to about 5% (wt/wt) or substantially pured-limonene from about 0.1% to about 5% (wt/wt) of the composition. Thenatural orange oil is typically present at about 1.6% (wt/wt) of saidcomposition and d-limonene is typically present at about 1.5% (wt/wt) ofthe composition.

In at least one embodiment, a pharmaceutical mixed-fatty-acidscomposition in which, a) at least 90% by weight of the composition iscomprised of long chain, polyunsaturated, Omega-3 fatty acids; b) atleast 80% by weight of the composition is comprised of a combination of(all-Z omega-3)-5,8,11,14,17-eicosapentaenoic acid (EPA) and (all-Zomega-3)-4,7,10,13,16,19-docosahexaenoic acid (DHA) in a weight ratio ofEPA:DHA of from 1:1 to 2:1, with the EPA constituting 40 to 60% byweight of the composition and the DHA constituting 25 to 45% by weightof the composition; c) at least 4.5% by weight of the composition iscomprised of Omega-3 fatty acids other than EPA and DHA that have 18,20, 21, or 22 carbon atoms; d) from 1 to 4% by weight of the compositionis comprised of (all-Z omega-3)-6,9,12,15,18-heneicosapentaenoic acid;e) at least one surface active agent; and f) the composition is in oraldosage form and includes an effective amount of a pharmaceuticallyacceptable antioxidant. These compositions can optionally furthercomprise natural orange oil from about 0.1% to about 5% (wt/wt) orsubstantially pure d-limonene from about 0.1% to about 5% (wt/wt) of thecomposition. The natural orange oil is typically present at about 1.6%(wt/wt) of said composition and d-limonene is typically present at about1.5% (wt/wt) of the composition.

It should be noted that in all of the embodiments comprisingcompositions described herein, the total of all ingredients comprisingthe composition does not exceed 100%.

In certain embodiments is provided, a pharmaceutical or drug compositioncomprising EPA and DHA in a weight to weight ratio of about 3.5:1 toabout 5:1 and at least one surface active agent, and wherein thecomposition is more than 84% combined EPA and DHA by weight. Thesecompositions can optionally further comprise natural orange oil fromabout 0.1% to about 5% (wt/wt) or substantially pure d-limonene fromabout 0.1% to about 5% (wt/wt) of the composition. The natural orangeoil is typically present at about 1.6% (wt/wt) of said composition andd-limonene is typically present at about 1.5% (wt/wt) of thecomposition.

Certain embodiments provide for certain compositions comprising at leastabout 96% by weight, ethyl eicosapentaenoate (ethyl-EPA), at least onesurface active agent, substantially no docosahexaenoic acid (DHA) or itsesters. These compositions can optionally further comprise naturalorange oil from about 0.1% to about 5% (wt/wt) or substantially pured-limonene from about 0.1% to about 5% (wt/wt) of the composition. Thenatural orange oil is typically present at about 1.6% (wt/wt) of saidcomposition and d-limonene is typically present at about 1.5% (wt/wt) ofthe composition.

In at least one embodiment, a method is provided for treating thefollowing disorders: metabolic syndrome, macular degeneration, Omega-3deficiency, cognitive impairment, including as a result of surgery ortraumatic brain injury (such as, for example, resulting from aconcussion), major depression, suicide, post-partum depression,inflammation, primary sclerosing cholangitis, borderline personalitydisorder in women, breast cancer, non-alcoholic fatty acid liverdisease, and improvement in cognition and behavior in children. Theseconditions or disorders can be treated by administering the compositionsdescribed herein to a subject, typically a human, in need of suchadministration.

In at least one embodiment, a method is provided for treating at leastone cardiovascular condition or disorder in a subject in need of suchtreatment, said method comprising administering to a subject at leastone composition described herein comprising a therapeutically effectiveamount of the Omega-3 fatty acid esters and at least one surface activeagent.

In at least one embodiment a method is provided for treating at leastone cardiovascular condition or disorder, for example and withoutlimitation disorders of the heart and vasculature, including, forexample, hypertension, hyperlipidemia, hypertriglyceridemia,atherosclerosis, transient ischemic attack, systolic dysfunction,diastolic dysfunction, aneurysm, aortic dissection, myocardial ischemia,acute myocardial infarction (AMI), acute ST-segment elevation myocardialinfarction (STEMI), acute non-ST-segment elevation myocardial infarction(NSTEMI), angina pectoris, unstable angina (UA), and stable angina (SA),myocardial infarction, congestive heart failure, dilated congestivecardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy,corpulmonale, arrhythmia, valvular heart disease, endocarditis,pulmonary embolism, venous thrombosis, peripheral vascular disease, andperipheral artery disease. The method comprises administering to asubject in need of treatment a therapeutically effective amount of acomposition described herein.

In at least one embodiment, a method is provided for treatinghypertension and/or hyperlipidemia.

In at least one other embodiment, a method is provided for treatinghypertriglyceridemia.

In certain embodiments, the total amount of triglycerides (TG) in ahuman subject's blood having 150 mg TG per dL of serum at the start ofthe dosing regimen is reduced by at least 20% within about 30 daysfollowing administration of certain embodiments of the compositionsdescribed herein.

In at least one other embodiment, a method is provided for treating ahuman subject having 150 mg TG per dL of serum who is in need of suchtreatment, said method comprising administering to the human subject atleast one embodiment of the composition described herein comprising atherapeutically effective amount of Omega-3 fatty acid esters.

Certain embodiments provide for a composition comprising EPA ethylester, DHA ethyl ester and at least one surface active agent, whereinsaid composition when administered to a patient in need of treatment forhypertriglyceridemia, provides for a reduction of circulatingtriglyceride blood plasma levels of at least 25% greater than thereduction of circulating triglyceride blood plasma levels provided bythe administration of LOVAZA® at equivalent dosage strengths of EPAethyl ester and DHA ethyl ester in said composition.

In certain embodiments, administration of the compositions comprisingEPA ethyl ester, DHA ethyl ester and at least one surface active agentcan reduce the circulating triglyceride blood plasma levels by 30%, 35%,40%, 45%, 50%, 55%, or 60% compared to the reduction in circulatingtriglyceride blood plasma levels observed by the administration ofLovaza® at equivalent dosage strengths of EPA ethyl ester and DHA ethylester in said composition.

Certain embodiments provide for a composition comprising EPA ethylester, DHA ethyl ester and at least one surface active agent, whereinsaid composition when administered to a patient in need of treatment forhypertriglyceridemia, provides for a mean reduction of circulatingtriglyceride blood plasma levels of at least 25% greater than the meanreduction of circulating triglyceride blood plasma levels provided bythe administration of LOVAZA® at equal dosage strengths of EPA ethylester and DHA ethyl ester in said composition.

In certain embodiments, the mean reduction of triglyceride levels isbased on a study involving at least 30 patients i.e., n=30.

In certain embodiments, the mean reduction of circulating triglycerideblood plasma levels is observed 7, 10, 13, 16, 19, 22, 25 or 28 daysafter the initial administration.

In certain embodiments, the mean reduction of circulating triglycerideblood plasma levels is observed 7 days after the initial administration.

In certain embodiments, the mean reduction of circulating triglycerideblood plasma levels is observed 28 days after the initialadministration.

In certain embodiments, the compositions of the invention areadministered to a patient having a mildly elevated base-line level ofcirculating triglycerides (271-368 mg/d L).

In certain embodiments, the compositions of the invention provide formean plasma concentrations of EPA and DHA total lipids that are about10-fold higher than those of an equivalent dose of Lovaza® in thefasting state.

In certain embodiments, the compositions of the invention provide for amean plasma concentrations of EPA and DHA total lipids that are about2-fold higher than those of an equivalent does of EPANOVA® and LOVAZA®in the fed state.

In certain embodiments, compositions comprising EPA ethyl ester, DHAethyl ester and at least one surface active agent, when administered toa patient in need of treatment for hypertriglyceridemia, provide for aC_(max) of total EPA and DHA total lipid plasma concentration that is atleast about 10-fold greater than the C_(max) of total EPA and DHA totallipid plasma concentration provided by an equivalent dosage of LOVAZA®when administered under fasted conditions.

In certain embodiments, compositions comprising EPA ethyl ester, DHAethyl ester and at least one surface active agent, when administered toa patient in need of treatment for hypertriglyceridemia, provide for aC_(max) of total EPA and DHA total lipid plasma concentration that is atleast about 1.5 times greater than the C_(max) of total EPA and DHAtotal lipid plasma concentration provided by an equivalent dosage ofLOVAZA® or EPANOVA® when administered under fed conditions.

Certain embodiments of the invention provide for dosage strengths of EPAand DHA ethyl esters that are equivalent to the dosage strengths ofLOVAZA® or EPANOVA® in the fed state.

Certain embodiments of the invention provide for dosage strengths of EPAand DHA ethyl esters that are equivalent to the dosage strengths ofLOVAZA® in the fasted state.

Certain embodiments of the invention provide for dosage strengths of EPAand DHA ethyl esters that are equal to the dosage strengths of LOVAZA®or EPANOVA® in the fed state.

Certain embodiments of the invention provide for dosage strengths of EPAand DHA ethyl esters that are equal to the dosage strengths of LOVAZA®in the fasted state.

Embodiments are also provided wherein the compositions described hereinare packaged together as a kit with instructions on how to use thecompositions for treating cardiovascular conditions or disorders.

In certain embodiments, the surface active agent is selected from thegroup consisting of at least one nonionic surface active agents,cationic surface active agents, anionic surface active agents,zwitterionic surface active agents, or combinations thereof.

In certain embodiments, the surface active agent is selected from thegroup consisting of at least one anionic surface active agent, at leastone non-ionic surface active agent, and a combination thereof.

In certain embodiments comprising at least one surface active agent, theat least one surface active agent has a hydrophilic-lipophilic balance(HLB) of about 8.0.

In certain embodiments comprising at least one surface active agent, thesurface active agent can be a non-ionic surface active agent selectedfrom the group consisting of at least one polysorbate, at least onepoloxamer, and a combination thereof.

In certain embodiments, the at least one surface active agent comprisesa polysorbate present from about 15% wt/wt to about 31% wt/wt of thecomposition. In certain embodiments, the polysorbate is polysorbate 80.

In certain other embodiments, the at least one surface active agentcomprises a poloxamer present from about 0.1% to about 5% wt/wt of thecomposition.

In certain embodiments, the compositions described herein comprise acombination of polysorbate 80 and the poloxamer PLURONIC® F87[(HO(C2H4O)₆₄(C3H6O)₃₇(C2H4O)₆₄H]. It is to be understood thatthroughout this specification, any reference to PLURONIC® F87 alsoreferences its equivalent, Poloxamer 237.

In certain embodiments, the composition further comprises at least oneantioxidant. In such embodiments the at least one antioxidant isselected from the group consisting of a tocopherol, a tocotrienol, orcombinations thereof. In such embodiments, the tocopherol, tocotrienolor combinations thereof is present from about 0.01% to about 5% byweight of the compositions. In certain such embodiments, thetocopherols, tocotrienols or combinations thereof can be present atabout 0.01%, 0.05%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%,0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% by weight of thecompositions. In certain such embodiments, the tocopherols,tocotrienols, or combinations thereof can be present at about 0.4% byweight of the compositions. In certain embodiments, the tocopherol,tocotrienol or combinations is present at about 0.4% by weight of thecomposition. In certain embodiments further comprising at least oneantioxidant, the antioxidant is a tocopherol at about 0.4% by weight ofthe composition.

In certain embodiments, the composition self-micellizes in an aqueousmedium. In certain other embodiments, the aqueous medium is water. Incertain other embodiments, the aqueous medium has an acidic pH. Incertain other embodiments, the aqueous medium is 0.1N HCl.

In certain embodiments, the compositions described hereinself-micellizes in an aqueous medium wherein the micelles have adiameter from about 1 μm to about 10 μm. In certain embodiments, thecompositions described herein self-micellizes in an aqueous mediumhaving an acidic pH, wherein the micelles have a diameter from about 1μm to about 10 μm. In certain other embodiments, the compositionsdescribed herein self-micellizes in 0.1N HCL, wherein the micelles havea diameter from about 1 μm to about 10 μm. In certain embodiments, themicelles have an average diameter of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 μm.

In certain embodiments, the compositions described herein can beadministered with or without food to a human subject in need of suchadministration wherein the bioavailability of the Omega-3 fatty acidesters comprising the compositions are substantially independent of foodeffect.

Certain embodiments provide for compositions that minimize or eliminateat least one side effect from the administration of a composition of thepresent disclosure when compared to the administration of a compositioncomprising Omega-3 fatty acid esters substantially free of a surfaceactive agent. In other embodiments, non-limiting examples of the sideeffects include regurgitation, frequency of burping, gastroesophagealreflux disease (GERD), bloating, increased intestinal gas, fish taste,fishy breath, fish smell, nausea, diarrhea, or combinations thereof.

In certain embodiments, the compositions described herein comprised-limonene or natural orange oil. Such compositions can minimize oreliminate at least one side effect from the administration of acomposition of the present disclosure when compared to theadministration of a composition comprising Omega-3 fatty acid esterssubstantially free of d-limonene or natural orange oil. In otherembodiments, non-limiting examples of the side effects includeregurgitation, frequency of burping, gastroesophageal reflux disease(GERD), bloating, increased intestinal gas, fish taste, fishy breath,fish smell, nausea, diarrhea, or combinations thereof.

In certain embodiments, the compositions described herein whenadministered to a human subject selected from the group consisting ofindividuals having from about 155 to about 199 mg TG per dL of serum,from about 200 to about 499 mg TG per dL of serum and from about 500 mgor higher TG per dL of serum, lowers said subject's serum TG levels byat least about 20%.

Certain embodiments of the compositions described herein can beadministered to a human subject in need of such administration with anon-Omega-3 fatty acid ester lipid-lowering agent selected from thegroup consisting of cholesterol absorption inhibitors, bile acidsequestrants/resins, statins, niacin and derivatives, MTP inhibitors,fibrates and CETP inhibitors.

In certain embodiments, the compositions described herein can reduce thetotal amount of TG in the serum of a human subject being treated forhypertriglyceridemia by at least about 20% within about 30 days ofadministration of the composition wherein the human subject's bloodmeasures 150 mg TG per dL of serum at the start of the dosing regimen.

In at least one embodiment, the compositions described herein can beadministered orally or parenterally in a suitable dosage form. Whenadministered orally, the compositions described herein can beadministered, typically, but not necessarily, in the form of a gel orliquid capsule.

In certain other embodiments, methods are provided for administering atleast about 0.5 g/day of certain embodiments of the compositionsdescribed herein comprising from about 40% to about 85% by weight of thecomposition, at least one EPA ester and at least one DHA ester in aratio of more than 2:1 to not more than 3.4:1 and at least one surfaceactive agent. Typically, but not necessarily, the ester is an ethylester and the at least one surface active agent is polysorbate 80,PLURONIC® F87 or a combination thereof. In certain such embodiments, theEPA and DHA ethyl esters combined comprise about 50% (wt/wt) of saidcomposition. Optionally, the composition can further comprisesubstantially pure d-limonene or natural orange oil.

In certain other embodiments, methods are provided for administering atleast about 4 g/day of certain embodiments of the compositions describedherein comprising ethyl eicosapentaenoic acid (ethyl-EPA), at least onesurface active agent and substantially no docosahexaenoic acid (DHA),where the ethyl-EPA constitutes at least about 96% by weight of thetotal Omega-3 fatty acid esters in the composition. In certainembodiments, such compositions can further comprise natural orange oilor substantially pure d-limonene.

Certain embodiments provide for the use of the compositions describedherein in the manufacture of a medicament for the treatment of acardiovascular disease or disorder. In certain embodiments, thecardiovascular disease or disorder is hyperlipidemia. In certain otherembodiments, the cardiovascular disease or disorder ishypercholesterolemia. In certain embodiments, the cardiovascular diseaseor disorder is hypertriglyceridemia.

Certain embodiments provide for the use of the compositions describedherein in the manufacture of a medicament for the treatment of acardiovascular disease or disorder. In certain embodiments, thecardiovascular disease or disorder is hyperlipidemia. In certain otherembodiments, the cardiovascular disease or disorder ishypercholesterolemia. In certain embodiments, the cardiovascular diseaseor disorder is hypertriglyceridemia.

In certain embodiments, administration of the compositions describedherein provide for a blood serum concentration in a human subject of atleast about 20 nmol/mL of combined at least one EPA ester and at leastone DHA ester within about four hours after administration of thecertain embodiments.

Also provided are kits comprising compositions of the Omega-3 fatty acidesters as one or more unit dosage forms together with instructions onusing the dosage forms. In certain embodiments, the dosage formsdescribed herein can be packaged as blister packs or in bottles withinstructions for using the dosage forms. For example, the instructionscan be provided as a package insert or directly on a label attached tothe blister pack, bottle or on secondary packaging in which the blisterpack or bottle was provided to a human subject. The instructions caninclude, for example, dosing frequency, administration of the dosageforms with or without food, the active ingredients comprising the dosageforms, and the cardiovascular conditions or disorders that would benefitfrom administration of the dosage forms.

In certain embodiments kits are provided, wherein certain dosage formscomprising the compositions described herein can be packaged togetherwith other non-Omega-3 fatty acid ester lipid lowering agents. Thekit(s) comprise one or more unit dosage forms of certain embodiments ofthe compositions described herein together with one or more unit dosageforms comprising the non-Omega-3 fatty acid ester lipid-lowering agentstogether with instructions on using the dosage forms.

Certain embodiments provide for a functional food(s) for treating and/orpreventing CVD comprising the compositions described herein.

Certain embodiments provide methods of treating CVD by administering afunctional food comprising the compositions described herein.

Certain embodiments provide for a functional food(s) comprising thecompositions described herein, and methods to treat hypertriglyceridemiain a human subject.

Certain embodiments provide for pharmaceutical composition comprisingEPA ethyl ester, DHA ethyl ester and at least one surface active agent,wherein administration of said composition to a patient in need oftreatment for hypertriglyceridemia for a period of 28 days providescirculating HDL cholesterol that is equivalent to the circulating HDLlevel observed with the administration of a corn oil placebo at timeperiods selected from the group consisting of 7, 14, 21 and 28 daysfollowing initial administration.

Certain embodiments provide for a pharmaceutical composition comprisinga mixture of EPA ethyl ester and DHA ethyl ester and at least onesurface active agent; wherein said at least one surface active agentcomprises from about 0.5% (wt/wt) to about 5% (wt/wt) of a blockcopolymer of polyethylene glycol and polypropylene glycol polyoxamerhaving a chemical formula HO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H(PLURONIC® F87); wherein the surfactant HLB value is about 15 to about17, wherein the composition is formulated in the form of a capsule, andwherein said composition is free of omega-3 free fatty acids, andwherein administration of said composition to a patient in need oftreatment for hypertriglyceridemia for a period of 28 days providescirculating HDL cholesterol that are equivalent to the circulating HDLlevel observed with the administration of a corn oil placebo at timeperiods selected from the group consisting of 7, 14, 21 and 28 daysfollowing initial administration.

Certain embodiments provide for a pharmaceutical composition comprisingEPA ethyl ester, DHA ethyl ester and at least one surface active agent,wherein administration of said composition to a patient in need oftreatment for hypertriglyceridemia provides equivalent circulating HDLlevels in said patient compared to subjects receiving an administrationof a corn oil placebo (in a 2-way cross over study).

Certain embodiments provide for a pharmaceutical composition comprisinga mixture of EPA ethyl ester and DHA ethyl ester and at least onesurface active agent; wherein said at least one surface active agentcomprises from about 0.5% (wt/wt) to about 5% (wt/wt) of a blockcopolymer of polyethylene glycol and polypropylene glycol polyoxamerhaving a chemical formula HO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H(PLURONIC® F87); wherein the surfactant HLB value is about 15 to about17, wherein the composition is formulated in the form of a capsule, andwherein said composition is free of omega-3 free fatty acids, andwherein administration of said composition to a patient in need oftreatment for hypertriglyceridemia provides equivalent circulating HDLlevels in said patient compared to subjects receiving an administrationof a corn oil placebo (in a 2-way cross over study).

Certain embodiments provide for a pharmaceutical composition comprisingEPA ethyl ester, DHA ethyl ester and at least one surface active agent,wherein said composition is administered to a patient in need oftreatment for hypertriglyceridemia provides maximum triglyceridereduction within 14 days of treatment compared to triglyceride reductionin a subject administered a corn oil placebo when both said compositionand placebo are administered under fasted conditions.

Certain embodiments provide for a pharmaceutical composition comprisinga mixture of EPA ethyl ester and DHA ethyl ester and at least onesurface active agent; wherein said at least one surface active agentcomprises from about 0.5% (wt/wt) to about 5% (wt/wt) of a blockcopolymer of polyethylene glycol and polypropylene glycol polyoxamerhaving a chemical formula HO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H(PLURONIC® F87); wherein the surfactant HLB value is about 15 to about17, wherein the composition is formulated in the form of a capsule, andwherein said composition is free of omega-3 free fatty acids, whereinsaid composition is administered to a patient in need of treatment forhypertriglyceridemia provides maximum triglyceride reduction within 14days of treatment compared to triglyceride reduction in a subjectadministered a corn oil placebo when both said composition and placeboare administered under fasted conditions.

Certain embodiments provide for a pharmaceutical composition comprisingEPA ethyl ester, DHA ethyl ester and at least one surface active agent,wherein said composition is administered to a patient in need oftreatment for hypertriglyceridemia provides maximum triglyceridereduction within 21 days of treatment compared to triglyceride reductionin a subject administered a corn oil placebo when both said compositionand placebo are administered under fasted conditions.

Certain embodiments provide for a pharmaceutical composition comprisinga mixture of EPA ethyl ester and DHA ethyl ester and at least onesurface active agent; wherein said at least one surface active agentcomprises from about 0.5% (wt/wt) to about 5% (wt/wt) of a blockcopolymer of polyethylene glycol and polypropylene glycol polyoxamerhaving a chemical formula HO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H(PLURONIC® F87); wherein the surfactant HLB value is about 15 to about17, wherein the composition is formulated in the form of a capsule, andwherein said composition is free of omega-3 free fatty acids, whereinsaid composition is administered to a patient in need of treatment forhypertriglyceridemia provides maximum triglyceride reduction within 21days of treatment compared to triglyceride reduction in a subjectadministered a corn oil placebo when both said composition and placeboare administered under conditions.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 depicts a photomicrograph of an embodiment. A compositioncomprising micelles, as described herein, was prepared, added between aslide and cover slip, observed at 40× magnification with a Nikon ModelTrinocular Head and a Spot RT3 digital camera, and the diameters ofseveral representative micelles were measured.

FIG. 2 shows a schematic flowchart of the process for manufacturing oneembodiment of the compositions described herein.

FIG. 3 shows a schematic flowchart of the process for manufacturing thegel mass for encapsulating one embodiment of the compositions describedherein.

FIG. 4 shows the a schematic flowchart of the encapsulation process formanufacturing one dosage form comprising one embodiment of thecompositions described herein.

FIGS. 5A and 58 show the mean individual EPA (A) and DHA (B) total lipidconcentration-time profiles (baseline-adjusted change) after a singledose of SC401 during fed and fasting conditions.

FIGS. 6A and 68 show the mean individual EPA (A) and DHA (B) free fattyacid concentration-time profiles (baseline-adjusted change) after asingle dose of SC401 during fed and fasting conditions.

FIG. 7 shows the mean individual EPA and DHA ethyl ester and free fattyacid concentration-time profiles (baseline-adjusted change) after asingle dose of SC401 during fed conditions.

FIG. 8 shows the geometric mean AUC_(0-t) of total and free fatty acidEPA and DHA concentrations during fasting conditions.

FIG. 9 shows the geometric mean AUC_(0-t) of total, ethyl esters, andfree fatty acid EPA and DHA concentrations during fed conditions.

FIG. 10 shows mean EPA and DHA total lipid plasma concentration profiles(μg/ml) (baseline-adjusted) after administration of a single dose (doseadjusted) of SC401, LOVAZA® and EPANOVA® in fed conditions.

FIG. 11 shows mean EPA and DHA total lipid plasma concentration profiles(μg/ml) (baseline-adjusted) after administration of a single dose (doseadjusted) of SC401 and LOVAZA® in fasted conditions.

DETAILED DESCRIPTION

As used herein the term, LOVAZA® is understood to include an Omega-3fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1.

As used herein, the term EPANOVA® is understood to include a combinationof EPA and DHA in free acid form.

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention, and is not intended to limit theinvention to the specific embodiments illustrated. Headings are providedfor convenience only and are not to be construed to limit the inventionin any manner. Embodiments illustrated under any heading may be combinedwith embodiments illustrated under any other heading.

The various embodiments of the invention described herein may suitablycomprise, consist essentially of, or consist of, at least one surfaceactive agent, at least one Omega-3 fatty acid (in either thetriglyceride, ester or free fatty acid form).

Certain aspects, modes, embodiments, variations and features of theinvention are described herein in various levels of detail to providefurther understanding of embodiments related to compositions comprisingOmega-3 fatty acid esters, and methods related to using suchcompositions containing a high concentration of Omega-3 fatty acidesters. In certain embodiments, an EPA ester and DHA ester are presentin specific weight ratio percentages and relative amounts. As noted,these compositions have beneficial effects on certain risk factors forCVD, including the lowering of serum triglycerides and serumcholesterol.

DEFINITIONS

As used herein, the term “composition(s)” or “formulation(s)” includestherapeutic and dietary compositions including, but not limited to adietary supplement, nutraceutical formulation, or pharmaceuticalformulation. Further, the terms composition, dietary supplement,nutraceutical formulation, and pharmaceutical formulation are usedinterchangeably herein.

As used herein, the term “EPA” refers inclusively to(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentenoic acid or derivativesthereof, including alkyl esters, such as, for example, the ethyl ester.

As used herein, the term “DHA” inclusively refers to(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid orderivatives thereof, including alkyl esters, such as, for example, theethyl ester.

As used herein, the term “micelle” (plural micelles, micella, ormicellae) refers to an aggregate of molecules, that have assembled intoan approximately spherical core/shell architecture, and are suspended inan aqueous phase. A typical micelle in aqueous solution forms anaggregate with the hydrophilic “head” regions in contact withsurrounding solvent and/or in contact with the polar region of one ormore surface active agent(s), sequestering the hydrophobic regions inthe micelle center. Micelles are approximately spherical in shape.

The term “self-micellizes” as used herein refers to the process in whichmicelles are formed in an aqueous medium without the introduction ofenergy, including agitation or shearing.

As used herein, the term “aqueous medium” refers to any solution orsuspension, that comprises water, including for example, withoutlimitation, water by itself; phosphate buffered saline pH 7.4, Sprite,apple juice, G-2 fruit punch, and chocolate milk. In certainembodiments, an aqueous medium comprises at least one fluid having anacidic pH. In certain other embodiments, an aqueous medium comprises abiological fluid such as, for example and without limitation, stomachacid. In other embodiments, the aqueous medium comprises simulatedstomach acid comprising 0.1N HCl.

As used herein, the term “free fatty acid” refers to one or morepolyunsaturated fatty acids that have not been modified or do not haveany other groups attached.

As used herein, the term “ester” refers to the replacement of thehydrogen in the carboxylic acid group of a polyunsaturated fatty acidmolecule with another substituent. Typical esters are known to those inthe art, a discussion of which is provided by Higuchi, T. et al.,Pro-drugs as Novel Delivery Systems, Vol. 14, A.C.S. Symposium Series,Bioreversible Carriers in Drug Design, Ed. Edward B. Roche, Amer.Pharma. Assoc., Pergamon Press (1987), and Protective Groups in OrganicChemistry, McOmie ed., Plenum Press, New York (1973), each of which isincorporated herein by reference in the entirety. Examples of commonesters include methyl, ethyl, trichloroethyl, propyl, butyl, pentyl,tert-butyl, benzyl, nitrobenzyl, methoxybenzyl, benzhydryl,monoglyceride, diglyceride, triglyceride.

As used herein, the term “monoglyceride” refers to a fatty acid chain,such as DHA or EPA molecule, covalently bonded to a glycerol moleculethrough an ester linkage. As used herein, the term “diglyceride” refersto a fatty acid chain such as DHA or EPA, covalently bonded to aglycerol molecule through an ester linkage, wherein the glycerolmolecule is further bonded to one additional fatty acid chain, which mayor may not be DHA or EPA, through one additional ester linkage. As usedherein, the term “triglyceride” refers to a fatty acid chain, such asDHA or EPA, covalently bonded to a glycerol molecule through an esterlinkage, wherein the glycerol molecule is further bonded to twoadditional fatty acid chains, either or both of which may or may not beDHA or EPA, through two additional ester linkages.

As used herein, the term “terpene” refers to the large and diverse classof organic compounds produced by a variety of plants, particularlyconifers. When terpenes are modified chemically, such as by oxidation orrearrangement of the carbon skeleton, the resulting compounds aregenerally referred to as “terpenoids” (e.g., carvone). Terpenes andterpenoids are the primary constituents of the essential oils of manytypes of plants and flowers.

As used herein, the terms “α-Tocopherol,” “tocopherol,” and “vitamin E”each refer to a set of tocopherols and tocotrienols, which arefat-soluble vitamins with antioxidant properties.

As used herein, the term “antioxidant” refers to a molecule capable ofinhibiting the oxidation of other molecules. Oxidation is a chemicalreaction that transfers electrons or hydrogen from a substance to anoxidizing agent. Oxidation reactions can produce free radicals. In turn,these radicals can start chain reactions. When the chain reaction occursin a cell, it can cause damage or death to the cell. Antioxidantsterminate these chain reactions by removing free radical intermediates,and inhibit other oxidation reactions. They do this by being oxidizedthemselves, so antioxidants are often reducing agents such as thiols,ascorbic acid, or polyphenols. Exemplary antioxidants include rosemaryoil, ascorbic acid (vitamin C), glutathione, lipoic acid, uric acid,carotenes, melatonin, ubiquinol (coenzyme Q), α-tocopherol (vitamin E),acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, and potassium metabisulfite.

As used herein, a pharmaceutically acceptable “carrier” refers to anysubstance suitable as a vehicle for delivering a molecule or compositionto a suitable in vivo site of absorption. Examples of such carriersinclude, but are not limited to water, phosphate buffered saline (PBS),Ringer's solution, dextrose solution, serum-containing solutions, Hank'ssolution and other aqueous physiologically-balanced solutions.

As used herein, a pharmaceutically acceptable “preservative” includesbut is not limited to potassium sorbate, methylparaben, propylparaben,benzoic acid and its salts, other esters of parahydroxybenzoic acid suchas butylparaben, alcohols such as ethyl or benzyl alcohol, phenoliccompounds such as phenol, or quarternary compounds such as benzalkoniumchloride.

As used herein, a “coloring agent” provides coloration to thecomposition or dosage form. Such coloring agents include food gradedyes.

As used herein, the term “subject” refers to a mammal, including but notlimited to a dog, cat, horse, cow, pig, sheep, goat, chicken, rodent,primate or human. Subjects include animals such as house pets (e.g.,dogs, cats, and the like), agricultural stock subjects (e.g., cows,horses, pigs, chickens, etc.), laboratory subjects (e.g., mice, rats,rabbits, etc.), but are not so limited. The human subject may be apediatric, adult, or a geriatric subject. The human subject may be ofeither gender.

As used herein, the terms “cardiovascular disease” and “cardiovascularcondition” include disorders of the heart and vasculature, including,for example, hypertension, hyperlipidemia, hypertriglyceridemia,atherosclerosis, transient ischemic attack, systolic dysfunction,diastolic dysfunction, aneurysm, aortic dissection, myocardial ischemia,acute myocardial infarction (AMI), acute ST-segment elevation myocardialinfarction (STEMI), acute non-ST-segment elevation myocardial infarction(NSTEMI), angina pectoris, unstable angina (UA), and stable angina (SA),myocardial infarction, congestive heart failure, dilated congestivecardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy,corpulmonale, arrhythmia, valvular heart disease, endocarditis,pulmonary embolism, venous thrombosis, peripheral vascular disease, andperipheral artery disease.

Hypertriglyceridemia, for example, is a condition related tocardiovascular disease in which fasting blood serum concentrations oftriglycerides are 150 mg/dL. Blood concentrations can rise frommoderately high levels of 200 mg/dL to 500 mg/dL, or in severe cases,above 500 mg/dL. The American Heart Association has categorizedtriglyceride concentrations as “normal” (below 150 mg/dL), “elevated”(150 to 199 mg/dL), “high” (200 to 499 mg/dL), and “very high” (above500 mg/dL). It will be evident to the skilled practitioner that thecategorization of hypertriglyceridemia can vary from country to country.For example, Canadian and European guidelines recommend fasting bloodserum triglyceride levels of less than 1.7 mmol/L as “desirable”, from1.7 to 2.2 mmol/L as “borderline high” and 2.3 to 5.6 mmol/L as “high”and above 5.6 mmol/L as “very high”. The skilled practitioner will alsoappreciate that what constitutes elevated blood serum triglyceridelevels may vary based on age and gender.

As used herein, an “effective amount” or “therapeutically effectiveamount” of a composition as described in some embodiments herein can bea quantity sufficient to achieve a desired therapeutic and/orprophylactic effect, for example, an amount which results in theprevention of, or a decrease in the symptoms associated with, a diseasethat is being treated. The amount of composition administered to thesubject, particularly one in need of the composition, can depend on thetype and severity of the disease and on the characteristics of theindividual, such as general health, age, sex, body weight and toleranceto drugs. A person skilled in the art will be able to determineappropriate dosages depending on these and other factors. Typically, aneffective amount of the compositions described herein can be sufficientfor achieving a therapeutic or prophylactic effect.

The terms “dose unit,” “unit dose,” and “dosage unit,” as used herein,refer to a portion of a composition that contains an effective amount ofan active suitable for a single administration to provide, or contributeto, a therapeutic effect. Such dosage units may be administered one to aplurality (i.e., 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) oftimes per day, or as many times as needed to elicit a therapeuticresponse.

The term “food effect,” as used herein, refers to a relative differencein AUC (area under the curve), C_(max) (maximum plasma concentration),and/or T_(max) (time to maximum concentration) of an active substance,when said substance or a composition thereof, such as a tablet, acapsule or a liquid, is administered orally to a subject concomitantlywith food or in a fed state as compared to the same values when the samecomposition is administered in a fasted state. The food effect, F, iscalculated as:

F=(Y _(fed) −Y _(fasted))/Y _(fasted)

wherein Y_(fed) and Y fasted are the found values of AUC, C_(max), orT_(max) in the fed and fasted state, respectively. A food effect, F, isgenerally established when F>1.

In general, the term “AUC” or “area under the plasma concentration-timecurve” is related to the total amount of an active measurable in thesystemic circulation following administration of a single dose. The AUCis a mathematical and visual representation of the aggregate amount ofthe active in the systemic circulation over a given period of time.Changes in the AUC need not necessarily reflect changes in the totalamount of the active absorbed but can reflect modifications in thekinetics of distribution, metabolism and excretion. Accordingly, theterm AUC as used herein refers to the total amount of Omega-3 fattyacids measurable in the systemic circulation following administration ofa single dose of any of the compositions described herein.

The term “T_(max) ^(”) or “time of peak concentration” refers to theperiod of time required to achieve peak plasma concentration of anactive after administration of a single dose. Accordingly, the termT_(max) as used herein refers to the period of time required to achievepeak plasma concentration of Omega-3 fatty acid esters afteradministration of a single dose of any of the compositions describedherein.

The term “C_(max) ^(”) or “peak concentration” is the highestconcentration of an active achieved in the blood plasma. Accordingly,the term C_(max) as used herein refers to the maximum concentration ofOmega-3 fatty acid esters after administration of a single dose of anyof the compositions described herein.

The term “substantially independent of a food effect,” or “substantiallyfree of food effect” as used herein, refers to a substantial eliminationof the effect of food upon the absorption (e.g., F is about 0),following oral administration, of any of the compositions describedherein. In other words, the bioavailability of the Omega-3 fatty acidesters, as measured by the logarithm-transformed AUC, is substantiallythe same regardless of whether the compositions described herein areadministered with or without food. In certain embodiments, thepharmacological effects of administration of compositions describedherein are substantially independent of a food effect.

The term “reduced food effect,” as used herein, as used herein, refersto a substantial reduction in the effect of food upon the absorption,following oral administration, of any of the compositions described. Incertain embodiments, the compositions described herein have a reducedfood effect.

The term “concomitantly with food” or “administration in the fed state,”as used herein, refers to administration from about 30 minutes before ameal to about 1 hour after a meal.

Various modes of treatment or prevention of medical conditions asdescribed herein are intended to mean “substantial” or “substantially”,which includes total but also less than total treatment or prevention,and wherein some biologically or medically relevant result is achieved.A subject, such as a human subject, in need of treatment refers to asubject in need of treatment of a defined disease state or in need ofpreventative treatment (i.e., prophylaxis) of such a disease state.

The term “about” or “approximately” as used herein means within anacceptable error range for the particular value as determined by one ofordinary skill in the art, which will depend in part on how the value ismeasured or determined, i.e., the limitations of the measurement system.Where particular values are described in the application and claims,unless otherwise stated, the term “about” means within an acceptableerror range for the particular value.

The term “active(s)”, “active ingredient(s)”, “active agents” or“pharmaceutically active ingredient” means a chemical entity intended tofurnish pharmacological activity or to otherwise have direct effect inthe diagnosis, cure, mitigation, treatment or prevention of disease, orto have direct effect in restoring, correcting or modifyingphysiological functions in a subject.

The term “functional food” as used herein means any edible or drinkablefoods or dietary components (e.g., juices, milk, yogurt, butter,margarine, baking products) that are fortified or enhanced with any ofthe compositions described herein. The functional food can be, e.g.,solid, liquid, semisolid, or a combination thereof. The term “functionalfood” also encompasses edible and drinkable nutritional supplements.

The term “hydrophilic-lipophilic balance” or “HLB,” as used herein,refers to the relative affinity of a substance or composition foraqueous and oily phases. HLB values can be calculated based on methodsand equations known to those of ordinary skill in the art, such as thosedescribed in U.S. Pat. No. 5,585,192. Substances or compositionsgenerally have an average HLB of about 6 to about 20.Hydrophilic-lipophilic balance values can be determined in a variety ofthe formulas or experimental methods provided, for example, in U.S. Pat.No. 5,585,192.

The term “substantially pure” as used herein means at least 90% pure.

The term “fed” or “fed state” as used herein refers to theadministration of the compositions of the invention described hereinwith meal conditions that are expected to provide the greatest effectson GI physiology so that systemic drug availability is maximallyaffected as described in the FDA Guidance for Industry—Food-EffectBioavailability and Fed Bioequivalence Studies, December 2002.

The term “fasted” or “fasted state” as used herein refers to theadministration of the compositions of the invention described hereinfollowing an overnight fast of at least 10 hours and as described in theFDA Guidance for Industry—Food-Effect Bioavailability and FedBioequivalence Studies, December 2002.

The term “equivalent” as used herein refers to same clinical effect andsafety profile of two different compositions when administered topatients under the same conditions. The two different compositions maybe two different compositions of the invention described herein orcompositions of the invention and a placebo or prior art composition.

Pharmaceutical Compositions

In at least one embodiment, a composition is provided, wherein thecomposition comprises at least one Omega-3 fatty acid ester, at leastone surface active agent, and wherein the composition self-micellizeswhen in contact with an aqueous medium. In certain embodiments, said atleast one Omega-3 fatty acid ester comprises from about 40% (wt/wt) toabout 85% (wt/wt) of the composition. In certain embodiments, the atleast one Omega-3 fatty acid ester comprises about 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80% or 85% (wt/wt) of the composition.

In certain embodiments, the compositions described herein self-micellizein 0.1N HCl. It is well accepted that 0.1N HCl (simulated gastricfluid), serves as a proxy for the acidity of stomach contents.Accordingly, and without being bound by theory, it is believed that thecompositions described herein can self-micellize in situ in the stomachor small intestine. In certain embodiments, the compositions describedherein more efficiently and effectively deliver Omega-3 fatty acidesters through the intestinal tract when administered with or withoutfood.

Certain embodiments call for the use of Omega-3 fatty acid esters.Accordingly, in one aspect, a composition is provided comprising atleast one (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentenoic acid (EPA)ester; or at least one(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid (DHA)ester; or a combination thereof, wherein the composition has a ratio ofEPA ester to DHA ester of more than 2.0:1.0 to not more than 3.4:1.0 andis substantially free of active ingredients other than said Omega-3fatty acid esters. In certain embodiments, the Omega-3 fatty acid estersin said composition comprise Omega-3 fatty acid ethyl esters. In certainembodiments, the EPA and DHA esters constitute from at least about 40%to about 95% (wt/wt) of the total Omega-3 fatty acid esters in thecomposition. In certain embodiments, the EPA and DHA esters compriseabout 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%(wt/wt) of the total Omega-3 fatty acid esters of the composition.

It has been discovered that compositions comprising Omega-3 fatty acidesters having a ratio of more than 2.0:1.0 to not more than 3.4:1.0 ofalkyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentenoate to alkyl(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoate (EPA:DHA) areeffective for the reduction of TG concentrations in blood serum. Incertain embodiments, the EPA and DHA esters comprise at least 40% of thetotal Omega-3 fatty acid esters of the composition. In certainembodiments, the EPA and DHA esters comprise about 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the total Omega-3 fattyacid esters of the composition. It also has been discovered thatcompositions having Omega-3 fatty acid esters including more than about2.0:1.0 to not more than 3.4:1.0 (EPA:DHA esters) can be formulated withone or more surface active agents to produce compositions thatself-micellize in an aqueous medium. The micelles are generallyuniformly spherical and stable, and provide for absorption of theOmega-3 fatty acid esters substantially free of any food effect. Basedon the observation that the compositions described herein self-micellizein 0.1N HCl, it is believed that the compositions described herein willalso self-micellize in the stomach or small intestine. In certainembodiments, such compositions provide beneficial drug delivery profilesfor Omega-3 fatty acid esters.

In certain embodiments, the compositions described herein, comprisingEPA and DHA esters, eliminate many of the side effects commonlyassociated with administration of Omega-3 fatty acid esters. Thus, thecompositions described herein, comprising EPA and DHA esters, do nothave a bad smell, and/or produce an unpleasant aftertaste, and/or causeburping in the patient. In another aspect, a composition is providedcomprising at least one(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentenoic acid (EPA) ester; orat least one (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoicacid (DHA) ester; or a combination thereof, wherein the composition hasa ratio of EPA ester to DHA ester of more than about 2.0:1.0 to not morethan about 3.4:1.0, and at least one surface active agent; wherein saidEPA ester, DHA ester, or a combination thereof, comprises at least 40%of the total amount of Omega-3 fatty acid esters in said composition. Incertain embodiments, the Omega-3 fatty acid esters in said compositioncomprise Omega-3 fatty acid esters. In certain embodiments, the EPA andDHA esters constitute at least from about 40% to about 95% of the totalOmega-3 fatty acid esters of the composition. Accordingly, in certainembodiments, the EPA and DHA esters comprise about 40%, 45%, 50%, 55%,60%, 65%, 70%, 75%, 80%, 85%, 90% or 95% of the total Omega-3 fatty acidesters of the composition.

In certain embodiments, the composition is comprised of a combination of(all-Z omega-3)-5,8,11,14,17-eicosapentaenoic acids (EPA) and (all-Zomega-3)-4,7,10,13,16,19-docosahexaenoic acids (DHA) in a weight ratioof EPA:DHA of from about 1:2 to about 2:1. In certain embodiments,compositions comprising EPA:DHA in a ratio of from about 1:2 to about2:1 further comprise (all-Z omega-3)-6,9,12,15,18-heneicosapentaenoicacid in an amount of at least 1% by weight. In certain embodiments, the(all-Z omega-3)-6,9,12,15,18-heneicosapentaenoic acid is present in anamount from about 1% to about 4% (wt/wt) of the composition. In certainembodiments, compositions comprising EPA:DHA in a ratio of from about1:2 to about 2:1 can further comprise at least 3% by weight of thecomposition is comprised of Omega-3 fatty acids other than EPA and DHAthat have 18, 20, 21, or 22 carbon atoms. In certain embodiments atleast 4.5% by weight of said composition comprises Omega-3 fatty acidsother than EPA and DHA that have 18, 20, 21, or 22 carbon atoms. Incertain other embodiments comprising EPA:DHA in a ratio of 1:2 to 2:1Omega-3 fatty acids other than EPA and DHA can be present in an amountof at least 1.5% by weight of the total fatty acids. The (all-Zomega-3)-5,8,11,14,17-eicosapentaenoic acids (EPA) and (all-Zomega-3)-4,7,10,13,16,19-docosahexaenoic acids (DHA) comprise at least80% (wt/wt) of said compositions. In certain embodiments, the EPAconstitutes 40 to 60% by weight of the composition and the DHAconstitutes 25 to 45% by weight of the composition. In certainembodiments, at least 90% by weight of the composition is comprised oflong chain, polyunsaturated, Omega-3 fatty acids. These combinations ofOmega-3 fatty acids are formulated with at least one surface activeagent. In certain compositions, the at least one surface active agent isa combination of polysorbate 80 and a block copolymer of polyethyleneglycol and polypropylene glycol polyoxamer having a chemical formulaHO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H (PLURONIC® F87). The polysorbate80 can be present from about 15% (wt/wt) to about 31% (wt/wt) of saidcomposition and the block copolymer of polyethylene glycol andpolypropylene glycol polyoxamer having a chemical formulaHO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H (PLURONIC® F87) can be presentfrom about 0.5% (wt/wt) to about 5% (wt/wt) of said composition. Incertain embodiments, such compositions when administered to a human atequal dosage strengths provides for substantially the samebioavailability when administered with or without food to said human inneed of such administration.

In certain embodiments, the ratio of EPA ester to DHA ester is from morethan 2.0:1.0 to not more than 3.4:1.0. In certain embodiments, the ratioof EPA ester to DHA ester is from about 2.0:1 to about 3.4:1.0. In otherembodiments, the ratio of EPA ester to DHA ester is from about 2.0:1.0to about 3.0:1.0. In other embodiments, the ratio of EPA ester to DHAester is from about 2.0:1.0 to about 2.7:1.0. In other embodiments, theratio of EPA ester to DHA ester is from about 2.0:1.0 to about 2.5:1.0.In other embodiments, the ratio of EPA ester to DHA ester is from about2.0:1.0 to about 2.4:1.0. In other embodiments, the ratio of EPA esterto DHA ester is from about 2.1:1.0 to about 2.3:1.0. In otherembodiments, the ratio of EPA ester to DHA ester is from about 2.1:1.0to about 2.2:1.0. In other embodiments, the ratio of EPA ester to DHAester is about 2.4:1.0.

In certain embodiments, said ratio of EPA ester to DHA ester in saidcomposition is about 2.0:1.0. In certain embodiments, said ratio of EPAester to DHA ester in said composition is about 2.1:1.0. In certainembodiments, said ratio of EPA ester to DHA ester in said composition isabout 2.15:1.0. In certain embodiments, said ratio of EPA ester to DHAester in said composition is about 2.2:1.0. In certain embodiments, saidratio of EPA ester to DHA ester in said composition is about 2.3:1.0. Incertain embodiments, said ratio of EPA ester to DHA ester in saidcomposition is about 2.4:1.0. In certain embodiments, said ratio of EPAester to DHA ester in said composition is about 2.5:1.0. In certainembodiments, said ratio of EPA ester to DHA ester in said composition isabout 2.6:1.0. In certain embodiments, said ratio of EPA ester to DHAester in said composition is about 2.7:1.0. In certain embodiments, saidratio of EPA ester to DHA ester in said composition is about 2.8:1.0. Incertain embodiments, said ratio of EPA ester to DHA ester in saidcomposition is about 2.9:1.0. In certain embodiments, said ratio of EPAester to DHA ester in said composition is about 3.0:1.0. In certainembodiments, said ratio of EPA ester to DHA ester in said composition isabout 3.1 1.0. In certain embodiments, said ratio of EPA ester to DHAester in said composition is about 3.2:1.0. In certain embodiments, saidratio of EPA ester to DHA ester in said composition is about 3.3:1.0. Incertain embodiments, said ratio of EPA ester to DHA ester in saidcomposition is about 3.4:1.0.

In certain embodiments, the compositions described herein comprise anOmega-3 fatty acid ester selected from at least one of the followinghexadecatrienoic acid (“HTA” or 16:3 (n-3), or all—Z-7,10,13-hexadecatrienoic acid), a-linolenic acid (“ALA” or 18:3(n-3), or all-Z-9,12,15-octadecatrienoic acid), stearidonic acid (“SDA”or 18:4 (n-3) or all-Z-6,9,12,15-octadecatetraenoic acid),eicosatrienoic acid (“ETE” or 20:3 (n-3) or all-Z-11, 14, 17eicosatrienoic acid), eicosatetraenoic acid (“ETA” or 20:4 (n-3), orall-Z-8,11,14,17-eicosatetraenoic acid), eicosapentaenoic acid (“EPA” or20:5 (n-3) or all-Z-5,8,11,14,17-eicosapentaenoic acid),heneicosapentaenoic acid (“HPA” or 21:5 (n-3) orall-Z-6,9,12,15,18-heneicosapentaenoic acid), docosapentenoic acid(“DPA”, or clupanodonic acid or 22:5 (n-3) orall-Z-7,10,13,16,19-docosapentenoic acid); docosahexaenoic acid (“DHA”or 22:6 (n-3) or all-Z-4,7,10,13,16,19-docosahexaenoic acid),tetracosapentenoic acid (24:5 (n-3) orall-Z-9,12,15,18,21-tetracosapentenoic acid), tetracosahexaenoic acid(nisinic acid or 24:6 (n-3) or all-Z-6,9,12,15,18,21-tetracosahexaenoicacid. In certain embodiments provided herein, the esters comprise anester of (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentenoic acid (EPA),an ester of (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoicacid (DHA), or a combination thereof. In certain embodiments, the estersare ethyl esters. In certain embodiments, the esters are a singleOmega-3 fatty acid ester. In certain embodiments, the esters arecombinations of different Omega-3 fatty acid esters, such as thoserecited herein. In certain embodiments, other fatty acids, or dietaryoils can also be present.

In certain embodiments, said Omega-3 fatty acid ester(s) comprise about40% (wt/wt) of said composition. In certain embodiments, said Omega-3fatty acid ester(s) comprise at about 45% (wt/wt) of said composition.In certain embodiments, said Omega-3 fatty acid ester(s) comprise about50% (wt/wt) of said composition. In other embodiments, said Omega-3fatty acid ester(s) comprise about 55% (wt/wt) of said composition. Inother embodiments, said Omega-3 fatty acid ester(s) comprise about 60%(wt/wt) of said composition. In other embodiments, said Omega-3 fattyacid ester(s) comprise about 65% (wt/wt) of said composition. In otherembodiments, said Omega-3 fatty acid ester(s) comprise at about 70%(wt/wt) of said composition. In other embodiments, said Omega-3 fattyacid ester(s) comprise about 75% (wt/wt) of said composition. In otherembodiments, the Omega-3 fatty acid ester(s) comprise about 80% (wt/wt)of said composition. In other embodiments, the Omega-3 fatty acidester(s) comprise about 85% (wt/wt) of said composition. In otherembodiments, the Omega-3 fatty acid ester(s) comprise about 90% (wt/wt)of said composition. In other embodiments, the Omega-3 fatty acidester(s) comprise about 95% (wt/wt) of said composition.

In certain embodiments, the compositions comprise a pharmaceuticalcomposition comprising a first Omega-3 fatty acid ester selected fromthe group consisting of an ester of hexadecatrienoic acid, α-linolenicacid, stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid,heneicosapentaenoic acid, docosapentenoic acid, docosahexaenoic acid,tetracosapentenoic acid, tetracosahexaenoic acid, or combinationsthereof; and a second Omega-3 fatty acid ester selected from the groupconsisting of an ester of hexadecatrienoic acid, α-linolenic acid,stearidonic acid, eicosatrienoic acid, eicosapentaenoic acid,heneicosapentaenoic acid, docosapentenoic acid, docosahexaenoic acid,tetracosapentenoic acid, tetracosahexaenoic acid, or combinationsthereof and at least one surface active agent. The first and secondOmega-3 fatty acid esters to be selected will be different. The ratio ofthe first to second Omega-3 fatty acid esters should be from more than2:1 to not more than 3.4:1 (first Omega-3 fatty acid ester:secondOmega-3 fatty acid ester). Typically, the ratio of the first to secondOmega-3 fatty acid ester is about 2.4:1. The first and second Omega-3fatty acid esters combined comprise from about 40% to about 85% (wt/wt)of the composition. In certain embodiments, the first and second Omega-3fatty acid esters combined comprise at least about 40% (wt/wt) of thecomposition. In certain embodiments, the first and second Omega-3 fattyacid esters combined comprise at least about 45% (wt/wt) of thecomposition. In certain embodiments, the first and second Omega-3 fattyacid esters combined comprise at least about 50% (wt/wt) of thecomposition. In certain embodiments, the first and second Omega-3 fattyacid esters combined comprise at least about 55% (wt/wt) of thecomposition. In certain embodiments, first and second Omega-3 fatty acidesters combined comprise at least about 60% (wt/wt) of the composition.In certain embodiments, the first and second Omega-3 fatty acid esterscombined comprise at least about 65% (wt/wt) of the composition. Incertain embodiments, the first and second Omega-3 fatty acid esterscombined comprise at least about 70% (wt/wt) of the composition. Incertain embodiments, first and second Omega-3 fatty acid esters combinedcomprise at least about 75% (wt/wt) of the composition. In certainembodiments, first and second Omega-3 fatty acid esters combinedcomprise at least about 80% (wt/wt) of the composition. In certainembodiments, first and second Omega-3 fatty acid esters combinedcomprise at least about 85% (wt/wt) of the composition. In certainembodiments, these mixed Omega-3 fatty acid ester compositions aresubstantially free of active ingredients other than said Omega-3 fattyacid esters. These mixed Omega-3 fatty acid ester compositions canfurther comprise at least one terpene and/or at least one antioxidant.The terpene is typically substantially pure d-limonene and is presentfrom about 0.1% to about 5% (wt/wt) of said composition. Optionally, thecomposition can also further comprise natural orange oil from about 0.1%to about 5% (wt/wt) of said composition. The at least one surface activeagent can be any one or more of the surface active agents describedherein, but is typically a polysorbate and/or a poloxamer, such as forexample, polysorbate 80 and PLURONIC® F87. The surface active agent ispresent from about 15% to about 31% (wt/wt) of the composition. Theantioxidant(s) suitable for use in these mixed Omega-3 fatty acid estercompositions, include, but are not limited to tocopherols and/ortocotrienols and can be present from about 0.01% to about 5% (wt/wt) ofthe composition. In certain such embodiments, the tocopherols and/ortocotrienols can be present at about 0.01%, 0.05%, 0.1%, 0.2%, 0.3%,0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%,4.5% or 5% by weight of the compositions. In certain such embodiments,the antioxidant is a tocopherol present at about 0.4% by weight of thecomposition.

In certain embodiments, compositions comprise an Omega-3 fatty acidester, such as an ethyl ester, one or more surface active agents. Incertain embodiments, said surface active agent is selected from thegroup consisting of nonionic surface active agents, cationic surfaceactive agents, anionic surface active agents, zwitterionic surfaceactive agents, or combinations thereof. In some embodiments, thecompositions include one or more non-ionic surface active agents.Non-ionic surface active agents generally have a hydrophobic group and areactive hydrogen atom, for example aliphatic alcohols, acids, amidesand alkyl phenols, with alkylene oxides, especially ethylene oxideeither alone or in combination with propylene oxide. Examples ofnonionic surfactant compounds include, but are not limited to,polyoxyethylene glycol sorbitan alkyl esters, block copolymers ofpolyethylene glycol and polypropylene glycol, ethylene glycol fatty acidesters, poly(ethylene glycol) fatty acid esters, propylene glycol fattyacid esters, poly(propylene glycol) fatty acid esters, glycol fatty acidesters, trimethylolpropane fatty acid esters, pentaerythritol fatty acidesters, glucoside derivatives, glycerin alkyl ether fatty acid esters,trimethylolpropane oxyethylene alkyl ethers, fatty acid amides,alkylolamides, alkylamine oxides, lanolin and its derivatives, castoroil derivatives, hardened castor oil derivatives, sterols and itsderivatives, polyoxyethylene alkyl ethers, polyoxyethylene alkyl allylethers, polyoxyethylene alkylamine, polyoxyethylene fatty acid amides,polyoxyethylene alkylolamides, polyoxyethylene diethanolamine fatty acidesters, polyoxyethylene trimethylolpropane fatty acid esters,polyoxyethylene alkyl ether fatty acid esters, polyoxyethylenepolyoxypropylene glycols, polyoxyethylene polyoxypropylene alkyl ethers,polyoxyethylene polyoxypropylene polyhydric alcohol ethers, glycerinfatty acid esters, polyglycerin fatty acid esters, polyoxyethyleneglycerin fatty acid esters, sorbitan fatty acid esters, polyoxyethylenesorbitan fatty acid esters, sucrose fatty acid esters, or combinationsthereof.

In certain embodiments, the surface active agents comprisepolyoxyethylene glycol sorbitan alkyl esters, block copolymers ofpolyethylene glycol and polypropylene glycol, or combinations thereof.

Examples of polyoxyethylene glycol sorbitan alkyl esters are typicallythe polysorbates. Polysorbates are a class of oily liquids derived fromPEG-ylated sorbitan (a derivative of sorbitol) esterified with fattyacids. Common brand names for polysorbates include TWEEN®. TWEEN®-20,TWEEN®-60 and TWEEN®-80, for example, are available from AkzoNobel(Strawinskylaan 2555 1077 ZZ, Amsterdam, the Netherlands). Exemplarypolysorbates include polysorbate 20 (polyoxyethylene (20) sorbitanmonolaurate), polysorbate 40 (polyoxyethylene (20) sorbitanmonopalmitate), polysorbate 60 (polyoxyethylene (20) sorbitanmonostearate), and polysorbate 80 (polyoxyethylene (20) sorbitanmonooleate).

Examples of block copolymers of polyethylene glycol and polypropyleneglycol include the poloxamers. Poloxamers are nonionic triblockcopolymers composed of a central hydrophobic chain of polyoxypropylene(poly(propylene oxide)) flanked by two hydrophilic chains ofpolyoxyethylene (poly(ethylene oxide)). Certain poloxamers, such asthose listed herein, are also known by the trade names PLURONIC®available from suppliers such as BASF AG (Ludwigshafen, Germany).Because the lengths of the polymer blocks can be customized, manydifferent poloxamers exist that have slightly different properties.Further exemplary PLURONIC® poloxamers include, but are not limited toPLURONIC® 10R5, PLURONIC® 17R2, PLURONIC® 17R4, PLURONIC® 25R2,PLURONIC® 25R4, PLURONIC® 31R1, PLURONIC® F 108 Cast Solid Surfacta,PLURONIC® F 108 NF, PLURONIC® F 108 Pastille, PLURONIC® F 108 Prill,PLURONIC® F 108NF Prill Poloxamer 338, PLURONIC® F 127, PLURONIC® F 127Prill, PLURONIC® F 127 NF, PLURONIC® F 127 NF 500 BHT Prill, PLURONIC® F127 NF Prill Poloxamer 407, PLURONIC® F 38, PLURONIC® F 38 Pastille,PLURONIC® F 68, PLURONIC® F 68 Pastille, PLURONIC® F 68 LF Pastille,PLURONIC® F 68 NF, PLURONIC® F 68 NF Prill Poloxamer 188, PLURONIC® F 68Prill, PLURONIC® F 68 Prill, PLURONIC® F 77, PLURONIC® F 77Micropastille, PLURONIC® F 87, PLURONIC® F 87 NF, PLURONIC® F 87 NFPrill Poloxamer 237, PLURONIC® F 87 Prill, PLURONIC® F 88, PLURONIC® F88 Pastille, PLURONIC® F 88 Prill, PLURONIC® F 98, PLURONIC® F 88 Prill,PLURONIC® F 98, PLURONIC® F 98 Prill, PLURONIC® L 10, PLURONIC® L 101,PLURONIC® L 121, PLURONIC® L 31, PLURONIC® L 35, PLURONIC® L 43,PLURONIC® L 44, PLURONIC® L 61, PLURONIC® L 62, PLURONIC® L 62 LF,PLURONIC® L 62D, PLURONIC® L 64, PLURONIC® L 81, PLURONIC® L 92,PLURONIC® L44 NF INH surfactant Poloxamer 124, PLURONIC® N 3, PLURONIC®P 103, PLURONIC® P 104, PLURONIC® P 105, Pluronic® P 123 Surfactant,Pluronic® P 65, Pluronic® P 84, Pluronic® P 85, or combinations thereof.

In certain embodiments, the composition comprises from about 15% (wt/wt)to about 31% (wt/wt) polysorbate. In certain embodiments, saidpolysorbate is polysorbate 80. In other embodiments, the compositioncomprises from about 0.5% (wt/wt) to about 5% (wt/wt) poloxamer. Incertain embodiments, the polysorbate is polysorbate 20, polysorbate 60,polysorbate 80 or a combination thereof, and the poloxamer is PLURONIC®F 87, PLURONIC® L61, PLURONIC® F 127, or a combination thereof. In someembodiments, the composition comprises Omega-3 fatty acid esters, suchas ethyl esters, in an amount from about 50% (wt/wt) to about 80%(wt/wt); and polysorbate from about 15% (wt/wt) to about 99% (wt/wt);and poloxamer from about 0.05% (wt/wt) to about 50% (wt/wt). In certainembodiments, the at least one surface active agent is a combination of apolysorbate, such as for example polysorbate 80, from about 15% (wt/wt)to about 31% (wt/wt) of said composition, and a poloxamer, such as forexample PLURONIC® F87, from about 0.5% (wt/wt) to about 5% (wt/wt) ofsaid composition.

In certain embodiments, said polysorbate comprises about 15% (wt/wt) toabout 70% (wt/wt) of said composition. In certain embodiments, saidpolysorbate comprises about 15% (wt/wt) to about 50% (wt/wt) of saidcomposition. In certain embodiments, said polysorbate comprises about15% (wt/wt) to about 31% (wt/wt) of said composition. In certainembodiments, said polysorbate comprises about 15% (wt/wt) to about 25%(wt/wt) of said composition. In certain embodiments, said polysorbatecomprises about 15% (wt/wt) to about 20% (wt/wt) of said composition. Incertain embodiments, said polysorbate comprises about 20% (wt/wt) toabout 31% (wt/wt) of said composition.

In certain embodiments, the poloxamer comprises from about 0.5% (wt/wt)to about 5% (wt/wt) of said composition. In certain embodiments, thepoloxamer comprises from about 0.5% (wt/wt) to about 4% (wt/wt) of saidcomposition. In certain embodiments, the poloxamer comprises from about0.5% (wt/wt) to about 3% (wt/wt) of said composition. In certainembodiments, the poloxamer comprises from about 0.5% (wt/wt) to about 2%(wt/wt) of said composition. In certain embodiments, the poloxamercomprises from about 0.5% (wt/wt) to about 1% (wt/wt) of saidcomposition.

In some embodiments, the compositions include one or more anionicsurface active agents. Exemplary “anionic surface active agents”include, but are not limited to, N-acyl-L-glutamic acid diethanolamine,N-acyl-L-glutamic acid triethanolamine, sodium N-acyl-L-glutamate,sodium alkanesulfonate, ammonium alkyl (C12, C14, C16) sulfate, alkyl(C11, C13, C15) sulfuric acid triethanolamine, alkyl (C11, C13, C15)sulfuric acid triethanolamine, alkyl (C12 to C14) sulfuric acidtriethanolamine, liquid alkylsulfuric acid triethanolamine, sodium alkyl(C12, C13) sulfate, liquid sodium alkylsulfate, sodium isoethionate,sodium lacto-isostearate, disodium undecylenoylamido ethylsulfosuccinate, triethanolamine sulfooleate, sodium sulfooleate,disodium oleamide sulfosuccinate, potassium oleate, sodium oleate,morpholine oleate, oleoyl sarcosine, oleoyl methyltaurine sodium salt,potassium-containing soap base, liquid base for potassium soap,potassium soap, carboxylated polyoxyethylene tridodecyl ether, sodiumsalt (3 ethyle oxide “E.O.”) of carboxylated polyoxyethylene tridodecylether, triethanolamine N-hydrogenated tallow fatty-acyl-L-glutamate,sodium N-hydrogenated tallow fatty-acyl-L-glutamate, sodium hydrogenatedcoconut fatty acid glyceryl sulfate, sodium diundecylenoylamido ethylsulfosuccinate, sodium stearyl sulfate, potassium stearate,triethanolamine stearate, sodium stearate, sodiumN-stearoyl-L-glutamate, disodium stearoyl-L-glutamate, stearoylmethyltaurine sodium salt, sodium dioctyl sulfosuccinate, liquid sodiumdioctyl sulfosuccinate, liquid disodium polyoxyethylene monooleylamidosulfosuccinate (2 E.O.), disodium polyoxyethylene lauroyl ethanolamidesulfosuccinate (5 E.O.), disodium lauryl sulfosuccinate, diethanolamidecetyl sulfate, sodium cetyl sulfate, soap base, sodium cetostearylsulfate, triethanolamine tridecyl sulfate, potassium palmitate, sodiumpalmitate, palmitoyl methyltaurine sodium salt, liquid castor oil fattyacid sodium salt (30%), ammonium polyoxyethylene alkyl ether sulfate (3E.O.), liquid diethanolamine polyoxyethylene alkyl (C12, C13) ethersulfate, liquid triethanolamine polyoxyethylene alkyl ether sulfate (3E.O.), triethanolamine polyoxyethylene alkyl (C11, C13, C15) ethersulfate (1 E.O.), triethanolamine polyoxyethylene alkyl (C12, C13) ethersulfate (3 E.O.), liquid sodium polyoxyethylene alkyl ether sulfate (3E.O.), sodium polyoxyethylene alkyl (C11, C13, C15) ether sulfate (1E.O.), sodium polyoxyethylene alkyl (C11 to C15) ether sulfate (3 E.O.),sodium polyoxyethylene alkyl (C12, C13) ether sulfate (3 E.O.), sodiumpolyoxyethylene alkyl (C12 to C14) ether sulfate (3 E.O.), sodiumpolyoxyethylene alkyl (C12 to C15) ether sulfate (3 E.O.), disodiumpolyoxyethylene alkyl (C12 to C14) sulfosuccinate (7 E.O.), sodiumpolyoxyethylene undecyl ether sulfate, liquid sodium polyoxyethyleneoctyl phenyl ether sulfate, ammonium polyoxyethylene oleyl ethersulfate, disodium polyoxyethylene lauryl sulfosuccinate, sodiumpolyoxyethylene nonyl phenyl ether sulfate, sodium polyoxyethylenepentadecyl ether sulfate, triethanolamine polyoxyethylene myristyl ethersulfate, sodium polyoxyethylene myristyl ether sulfate, sodiumpolyoxyethylene myristyl ether sulfate (3 E.O.), liquid sodiumpolyoxyethylene lauryl ether acetate (16 E.O.), ammonium polyoxyethylenelauryl ether sulfate (2 E.O.), triethanolamine polyoxyethylene laurylether sulfate, sodium polyoxyethylene lauryl ether sulfate,diethanolamine myristyl sulfate, sodium myristyl sulfate, potassiummyristyl sulfate, sodium N-myristoyl-L-glutamate, sodiummyristoylmethylaminoacetate, liquid myristoyl methyl-alanine sodiumsalt, myristoyl methyltaurine sodium salt, medicinal soaps,triethanolamine/magnesium coco alkyl sulfate, triethanolamine N-coconutoil fatty-acyl-L-glutamate, sodium N-coconut oil fatty-acyl-L-glutamate,sodium coconut oil fatty acid ethyl ester sulfonate, coconut oil fattyacid potassium salt, liquid coconut oil fatty acid potassium salt,sodium N-coconut oil fatty/hydrogenated fatty-acyl-L-glutamate, coconutoil fatty acid sarcosine, coconut oil fatty acid sarcosinetriethanolamine salt, coconut oil fatty acid sarcosine sodium salt,coconut oil fatty acid triethanolamine salt, liquid triethanolamine saltof coconut oil fatty acid, coconut oil fatty acid sodium salt, coconutoil fatty acid methyl alanine sodium salt, liquid coconut oil fatty acidmethyl alanine sodium salt, coconut oil fatty acid methyltaurinepotassium salt, coconut oil fatty acid methyltaurine sodium salt, sodiumlaurylamino dipropionate, liquid sodium laurylamino dipropionate (30%),sodium lauryl sulfoacetate; sodium lauryl benzenesulfonate, laurylsulfate, ammonium lauryl sulate, potassium lauryl sulfate,diethanolamine lauryl sulfate, triethanolamine lauryl sulfate, sodiumlauryl sulfate, magnesium lauryl sulfate, monoethanolainine laurylsulfate, potassium laurate, lauric acid triethanolamine, liquid lauricacid triethanolamine, sodium laurate, lauric acid/myristic acidtriethanolamine, lauroyl-L-glutamic acid triethanolamine, sodiumN-lauroyl-L-glutamate, lauroyl sarcosine, lauroyl sarcosine potassium,liquid lauroyl sarcosine triethanolamine salt, lauroyl sarcosine sodium,liquid lauroyl methyl-.beta.-alanine sodium salt, lauroyl methyltaurinesodium salt, liquid lauroyl methyltaurine sodium salt, or combinationsthereof.

In certain embodiments, said anionic surfactant(s) comprise about 0.05%(wt/wt) to about 25% (wt/wt) of said composition. In certainembodiments, said anionic surfactant(s) comprise about 0.05% (wt/wt) toabout 15% (wt/wt) of said composition. In certain embodiments, saidanionic surfactant(s) comprise about 0.05% (wt/wt) to about 5% (wt/wt)of said composition. In certain embodiments, said anionic surfactant(s)comprise about 0.5% (wt/wt) to about 3% (wt/wt) of said composition. Incertain embodiments, said anionic surfactant(s) comprise about 0.7%(wt/wt) of said composition. In certain embodiments, said anionicsurfactant(s) comprise sodium lauryl sulfate.

In certain embodiments, compositions comprise an Omega-3 fatty acidester, such as an ethyl ester, and further comprise one or more surfaceactive agents. In certain embodiments, said surface active agent isselected from the group consisting of a polysorbate or a combination ofpolysorbates, and an anionic surfactant or a combination of anionicsurfactants, or a combination of said polysorbates and said anionicsurfactants. In other embodiments, the composition comprises from about15% (wt/wt) to about 31% (wt/wt) polysorbate. In certain embodiments,said polysorbate is polysorbate 80. In other embodiments, thecomposition comprises from about 0.5% (wt/wt) to about 5% (wt/wt)anionic surfactant(s). In certain embodiments, the polysorbate ispolysorbate 80, polysorbate 20, or a combination thereof, and theanionic surfactant is sodium lauryl sulfate. In some embodiments, thecomposition comprises Omega-3 fatty acid esters, such as ethyl esters,in an amount from about 40% (wt/wt) to about 85% (wt/wt); andpolysorbate from about 15% (wt/wt) to about 99% (wt/wt); and anionicsurfactant(s) from about 0.05% (wt/wt) to about 50% (wt/wt). In someembodiments, the composition comprises Omega-3 fatty acid esters, suchas ethyl esters, in an amount from about 50% (wt/wt) to about 80%(wt/wt) (90); and polysorbate from about 15% (wt/wt) to about 99%(wt/wt); and anionic surfactant(s) such as, for example, sodium laurylsulfate from about 0.05% (wt/wt) to about 2% (wt/wt). In someembodiments, the composition comprises about 0.7% (wt/wt) sodium laurylsulfate.

In certain embodiments, said poloxamer comprises about 0.05% (wt/wt) toabout 25% (wt/wt) of said composition. In certain embodiments, saidpoloxamer comprises about 0.05% (wt/wt) to about 15% (wt/wt) of saidcomposition. In certain embodiments, said poloxamer comprises about0.05% (wt/wt) to about 5% (wt/wt) of said composition. In certainembodiments, said poloxamer comprises about 0.5% (wt/wt) to about 3%(wt/wt) of said composition.

In some embodiments, the compositions include additional surface activeagents such as the zwitterionic and cationic surface active agents.Examples of such surface active agents include, but are not limited tothe bile acids (e.g., cholic acid, chenodeoxycholic acid, glycocholicacid, glycodeoxycholic acid, taurocholic acid, taurochenodeoxycholicacid, taurolithocholic acid, deoxycholic acid, lithocholic acid, andursodeoxycholic acid and salts thereof, e.g., sodium, potassium,lithium), natural emulsifiers (e.g. acacia, agar, alginic acid, sodiumalginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin,egg yolk, casein, wool fat, cholesterol, wax, and lecithin), long chainamino acid derivatives, high molecular weight alcohols (e.g. stearylalcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethyleneglycol distearate, glyceryl monostearate, and propylene glycolmonostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene,polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer),carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium,powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose,hydroxypropyl methylcellulose, methyl cellulose), polyoxyethylene esters(e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylenehydrogenated castor oil, polyethoxylated castor oil, polyoxymethylenestearate, and Solutol), sucrose fatty acid esters, polyethylene glycolfatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g.polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone),diethylene glycol monolaurate, triethanolamine oleate, sodium oleate,potassium oleate, ethyl oleate, oleic acid, ethyllaurate, sodium laurylsulfate, cetrimonium bromide, cetylpyridinium chloride, benzalkoniumchloride, docusate sodium or combinations thereof.

Without being bound to any particular theory, it is believed that thecompositions described herein will increase fatty acid absorption inindividuals being administered the compositions of the inventiondescribed herein. (see Example 5). This is because the compositionsdescribed herein comprising the Omega-3 fatty acid(s) and the at leastone surface active agent self-micellizes in a manner similar to that inthe body. When human beings eat, micelles are formed around the fats weingest. These natural micelles form in the presence of bile regardlessof the pH in the stomach or intestines. Natural micelles form aroundfats and digestive enzymes, entrapping both. Within the micelles, theenzymes quickly cleave the triglycerides (fats) or esters (fats) intofree fatty acids and monoglycerides. Natural micelles rupture when theycome in contact with the brush barrier of the intestinal wall. The freefatty acids and monoglycerides thus released spill onto the lining ofthe intestine and are absorbed. Natural human micelles that form aroundomega-3 fatty acids have two characteristics that limit theireffectiveness. First, the micelles form only when food is present.Second, these micelles are less effective in a low fat environment ascompared to a high fat environment and not effective at all in a no-fatenvironment.

In contrast to natural micelles, the formation of artificial micelleshas hitherto been very sensitive to the pH of the liquid in which theyare being created and to the presence of other substances in thatliquid. In addition, artificial micelles are in general fragile andbreak easily, making it difficult for them to deliver adequate amountsof free fatty acids and monoglycerides to the intestinal lining. Themicelles formed by the compositions described herein, however, overcomethe deficiencies of both artificial and natural human micelles in thedelivery of omega-3 fatty acids, while at the same time mimicking someof the characteristics of natural human micelles.

In at least one embodiment, the compositions described herein comprisingthe Omega-3 fatty acid(s) and the at least one surface active agent, forexample the combination of polysorbate 80 and PLURONIC®® F87,spontaneously form micelles when encountering aqueous liquids. Thesemicelles form regardless of the pH or the nature and concentration ofother suspended materials in the liquid, does not require bile to form,and forms micelles that remain stable almost indefinitely. The micellesform whether or not food is present or whether food that is present ishigh or low in fat. Like human micelles, the micelles formed by thecompositions described herein form around omega-3 fatty acids and entrapboth fats and enzymes, allowing rapid digestion and the formation offree fatty acids and monoglycerides. Without being held to any onetheory, it is believed that the micelles formed by the compositionsdescribed herein are similar in size as human micelles and share theability to rupture at the intestinal brush barrier. Without being heldto any one theory, it is believed that either by friction or a chemicalreaction, the micelle ruptures and spills its contents onto the liningof the intestines and the intestines absorb the Omega-3 fatty acids.

In certain embodiments, the compositions described herein self-micellizein an aqueous medium. The aqueous medium can include, for example, 0.1NHCl. It is well accepted that 0.1N HCl (simulated gastric fluid), servesas a proxy for the acidity of stomach contents. Accordingly, and withoutbeing bound by theory, it is believed that the compositions describedherein can self-micellize in situ in the stomach or small intestine. Incertain embodiments, the compositions described herein more efficientlyand effectively deliver Omega-3 fatty acid esters through the intestinaltract when administered with or without food.

In addition to forming micelles in situ, in other embodiments,compositions comprising micelles are provided, wherein the micelles areformed by the addition of an aqueous medium to a composition of any oneof the embodiments provided herein prior to administration of saidcomposition to a subject in need of treatment. Alternatively, micellescan also be formed when the compositions are added to an aqueous medium.In certain embodiments, the micelles have a diameter of up to 10 μm. Inother embodiments, substantially all of the micelles have an averagediameter of from 1 μm to 10 μm. In certain embodiments, the micelleshave an average diameter of, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9 or10 μm. In certain embodiments, said micelles are stable at ambienttemperature.

Compositions suitable for self-micellization as described hereingenerally have an HLB from about 12 to about 18. In certain embodiments,said compositions have an HLB from about 12.0 to about 14.0. In certainembodiments, said compositions have an HLB from about 13.0 to about14.0. In certain embodiments, said compositions have an HLB from about13.5 to about 13.8. The total HLB of all the surface active agents orsurfactants used in the composition is generally from about 12 to about18. In some embodiments, the total HLB of all surface active agents usedin the composition is generally from about 12 to about 15. In someembodiments, the total HLB of all surface active agents or surfactantsused in the composition is generally from about 13 to about 15.

In certain embodiments, the at least one surface active agent orsurfactant has a HLB of at least 8.0. In some embodiments, said surfaceactive agent(s) or surfactant(s) have a combined HLB in the range offrom about 13 to about 15. As the HLB value of the surface activeagent(s) or surfactant(s) increases, the amount of surface active agentor surfactant needs to be decreased, such that at an HLB of 17, onlyabout 25% (wt/wt) to about 42% (wt/wt) of surface active agent(s) orsurfactant(s) may be required.

In certain embodiments, the composition further comprises a terpene. Incertain embodiments, the terpene is d-limonene. In one embodiment, theterpene is a cyclic terpene. In one embodiment, the terpene isd-limonene ((+)-limonene), which is the (R)-enantiomer. In oneembodiment, the terpene is L-limonene, which is the (S)-enantiomer. Inone embodiment, the terpene is racemic limonene, known as dipentene. Inanother embodiment, the terpene is a terpenoid. In another embodiment,the terpene or terpenes are derived from a natural oil (e.g., a citrusoil such as orange oil). Other terpenes are contemplated, such asmonoterpenes (e.g., terpinenes, terpinolenes, phellandrenes, ormenthol), having structures that are similar to d-limonene. In certainembodiments, the compositions further comprise substantially pured-limonene from about 0.1% to about 5% by weight of the composition. Incertain other embodiments, the compositions further comprise naturalorange oil from about 0.1% to about 5% by weight of the composition.Compositions comprising d-limonene or orange oil can aid in theelimination and/or minimization of side effects from the oraladministration of Omega-3 fatty acid esters. Such side effects includeregurgitation, frequency of belching, gastroesophageal reflux disease(GERD), bloating, increased intestinal gas, fish taste, fishy breath,fish smell, nausea, diarrhea, or combinations thereof.

In other embodiments, the composition further comprises an antioxidant.In certain embodiments, the antioxidant is selected from the consistingof at least one tocopherol, at least one tocotirenol, or combinationsthereof. In other embodiments, the compositions described herein mayinclude one or more tocopherol(s). In embodiments further comprising theat least one or more antioxidant(s), the antioxidant(s) can be presentfrom about 0.01% to about 5% by weight of the compositions. In suchembodiments, the antioxidant(s) can be present at about 0.01%, 0.05%,0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%,2.5%, 3%, 3.5%, 4%, 4.5% or 5% by weight of the compositions. In certainembodiments, the antioxidant(s) can be present at about 0.4% by weightof the compositions.

In an at least one additional embodiment, compositions comprisingmicelles are provided, wherein the micelles are formed by the additionof an aqueous medium to a composition of any one of the embodimentsprovided herein prior to administration of said composition to a subjectin need of treatment. Alternatively, micelles can also be formed whenthe compositions are added to an aqueous medium. In certain embodiments,the micelles have a diameter of up to about 10 μm. In other embodiments,substantially all of the micelles have an average diameter of from about1 μm to about 10 μm. In certain embodiments, the micelles have anaverage diameter of about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 μm. In certainembodiments, said micelles are stable at room temperature. In certainembodiments, the composition forms micelles in an aqueous medium havingan acidic pH. In certain other embodiments, the compositions formmicelles in 0.1N HCl.

In another embodiment, a composition is provided, wherein saidcomposition comprises at least one(5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentenoic acid (EPA) ester andat least one (4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoicacid (DHA) ester, and wherein said composition has a ratio of EPA esterto DHA ester of more than 2.0:1.0 to not more than about 3.4:1.0,provided that the concentration of said EPA ester, DHA ester, or acombination thereof comprises from about 40% to about 85% by weight ofthe total amount of Omega 3 esters in said composition. In certainembodiments, the ratio of EPA ester to DHA ester is from about 2.0:1.0to about 2.5:1.0. In other embodiments, the ratio of EPA ester to DHAester is from about 2.1:1.0 to about 2.4:1.0. In other embodiments, theratio of EPA ester to DHA ester is from about 2.1:1.0 to about 2.3:1.0.In other embodiments, the ratio of EPA ester to DHA ester is from about2.1:1.0 to about 2.2:1.0. In certain embodiments, said ratio of EPAester to DHA ester in said composition is 2.4:1.0. In other embodiments,the ratio of EPA ester to DHA ester is from about 2.0:1.0 to about3.3:1.0. In other embodiments, the ratio of EPA ester to DHA ester isfrom about 2.2:1.0 to about 3.2:1.0. In other embodiments, the ratio ofEPA ester to DHA ester is from about 2.4:1.0 to about 3.1:1.0. In otherembodiments, the ratio of EPA ester to DHA ester is from about 2.5:1.0to about 3.0:1.0. In other embodiments, the ratio of EPA ester to DHAester is from about 2.6:1.0 to about 2.9:1.0. In other embodiments, theratio of EPA ester to DHA ester is from about 2.7:1.0 to about 2.8:1.0.In certain embodiments, said ratio of EPA ester to DHA ester in saidcomposition is more than 2.0:1.0.

In certain embodiments, the Omega-3 fatty acid esters used herein aresubstantially pure. In certain embodiments, the Omega-3 fatty acidesters are from about 80% to about 99% pure. In certain embodiments, theOmega-3 fatty acid esters are at least 80%, 85%, 90%, 92%, 94%, 96%, 98%or 99% pure.

Methods for Treating Cardiovascular Conditions or Disorders

Methods are provided of treating one or more cardiovascular condition ordisorder in a subject in need of treatment, which method comprisesadministering to said subject a therapeutically effective amount of acomposition of any one of the embodiments provided herein, or a micelleof any one of the embodiments provided herein.

Accordingly, in certain embodiments, the cardiovascular condition ordisorder is of the heart and vasculature, including, for example,hypertension, hyperlipidemia, hypertriglyceridemia, atherosclerosis,transient ischemic attack, systolic dysfunction, diastolic dysfunction,aneurysm, aortic dissection, myocardial ischemia, acute myocardialinfarction (AMI), acute ST-segment elevation myocardial infarction(STEMI), acute non-ST-segment elevation myocardial infarction (NSTEMI),angina pectoris, unstable angina (UA), and stable angina (SA),myocardial infarction, congestive heart failure, dilated congestivecardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy,corpulmonale, arrhythmia, valvular heart disease, endocarditis,pulmonary embolism, venous thrombosis, peripheral vascular disease, andperipheral artery disease.

In particular embodiments, the cardiovascular condition or disorder ishypertension, hyperlipidemia, or a combination thereof. In otherembodiments, the cardiovascular condition or disorder ishypertriglyceridemia.

In another embodiment, a method is provided for treating moderate tosevere hypertriglyceridemia in a subject in need thereof, wherein themethod comprises providing a subject having a fasting baseline TG levelof about 200 mg/dL to about 500 mg/dL and administering to the subject acomposition as described herein. In one embodiment, the composition canbe administered in a daily amount of from about 0.5 g to about 1 g, fromabout 1 g to about 2 g, from about 2 g to about 4 g, from about 4 g toabout 6 g, or from about 6 g to about 10 g.

In certain embodiments, the amount of total fasting TG in the subject'sblood serum is reduced by at least 20% within thirty days ofadministration of said composition or said micelles in a subject havingat least 150 mg/dL fasting blood serum TG at the start of the dosingregimen. In other embodiments, the total concentration of low-densitylipoprotein (LDL) in said subject's blood serum does not substantiallyincrease within thirty days of administration of said composition orsaid micelles. In certain embodiments, the therapeutically effectiveamount of said composition or said micelles comprises at least 0.5 g/dayof the Omega-3 fatty acid esters. In other embodiments, said subject'sblood serum has a concentration of at least 20 nmol/mL of combined EPA,DHA or combinations thereof within four hours after administration ofsaid composition or said micelles.

In further embodiments, a method is provided of administering to asubject a composition comprising at least one Omega-3 fatty acid esterwherein the ratio of high-density lipoprotein is increased relative toLDL in the blood serum of the subject. In certain embodiments, theadministration is an oral administration. In certain embodiments, thesubject is a human.

Some embodiments provide for a method of administering to a subject acomposition comprising at least one Omega-3 fatty acid ester and atleast one surface active agent, wherein said at least one Omega-3 fattyacid ester self-micellizes when in contact with an aqueous medium, andsaid at least one Omega-3 fatty acid ester when orally administered isabsorbed by said subject at a rate that is substantially independent ofa food effect. In certain embodiments, the reduction of the food effectmay yield a reduction in F of at least 30%, at least 40%, at least 50%,or at least 75%.

A method is provided of administering to a subject a compositioncomprising at least one Omega-3 fatty acid ester and at least onesurface active agent, wherein said at least one Omega-3 fatty acid esterself-micellizes when in contact with an aqueous medium, and said atleast one Omega-3 fatty acid ester when orally administered is absorbedby said subject at a rate that is substantially independent of a foodeffect. In certain embodiments, said composition is a composition of anyone of the embodiments provided herein. In other embodiments, at least0.5 g/day of the Omega-3 fatty acid ester is administered to saidsubject.

In another embodiment, the composition as described herein isadministered, for example over a period of about 1 to about 200 weeks,about 1 to about 100 weeks, about 1 to about 80 weeks, about 1 to about50 weeks, about 1 to about 40 weeks, about 1 to about 20 weeks, about 1to about 15 weeks, about 1 to about 12 weeks, about 1 to about 10 weeks,about 1 to about 5 weeks, about 1 to about 2 weeks or about 1 week. Inanother embodiment, the composition as described herein is administeredfor an unlimited period of time to a subject in need of chronictreatment.

In other embodiments, said subject's blood serum has a concentration ofat least 20 nmol/mL of said at least one Omega-3 fatty acid ester withinfour hours after administration of said composition. In otherembodiments, said subject's blood serum has a concentration of at least50 nmol/mL of said at least one Omega-3 fatty acid ester within fourhours after administration of said composition. In other embodiments,said subject's blood serum has a concentration of at least 100 nmol/mLof said at least one Omega-3 fatty acid ester within four hours afteradministration of said composition. In other embodiments, theconcentration of said at least one Omega-3 fatty acid ester in saidsubject's blood serum can be increased upon the administration ofincreasing doses of said composition.

In certain embodiments, a method is provided of minimizing and/oreliminating side effects from the oral administration of Omega-3 fattyacid esters in the presence of a surface active agent to a subject inneed of treatment comprising administering a composition of any one ofthe embodiments provided herein or the micelles of any one of theembodiments provided herein. In certain embodiments, the method ofminimizing side effects eliminates the onset of side effects. In someembodiments, non-limiting examples of the side effects includeregurgitation, frequency of belching, gastroesophageal reflux disease(GERD), bloating, increased intestinal gas, fish taste, fishy breath,fish smell, nausea, diarrhea, or combinations thereof.

In certain embodiments, a method is provided of minimizing and/oreliminating side effects from the oral administration of Omega-3 fattyacid esters in the presence of at least one terpene or natural orangeoil to a subject in need of treatment comprising administering acomposition of any one of the embodiments provided herein or themicelles of any one of the embodiments provided herein. In certainembodiments, the at least one terpene is typically, but not necessarilyd-limonene that is at least 95% pure. In certain embodiments, the methodof minimizing side effects eliminates the onset of side effects. In someembodiments, non-limiting examples of the side effects includeregurgitation, frequency of belching, gastroesophageal reflux disease(GERD), bloating, increased intestinal gas, fish taste, fishy breath,fish smell, nausea, diarrhea, or combinations thereof.

Some embodiments provide for a method of reducing a food effect in asubject in need of treatment, which method comprises administering to ahuman subject a therapeutically effective amount of any one of thecompositions described herein. In certain embodiments, the food effectis substantially eliminated.

Methods are also provided for improving patient compliance during theoral administration of Omega-3 fatty acid esters to a subject in need oftreatment comprising administering a composition as described herein.

The compositions described herein can be administered to a human subjectin need of such administration with a non-Omega-3 fatty acid esterlipid-lowering or cholesterol lowering agent selected from the groupconsisting of cholesterol absorption inhibitors, bile acidsequestrants/resins, statins, niacin and derivatives, MTP inhibitors,fibrates and CETP inhibitors. These lipid-lowering or cholesterollowering agents can be categorized by their mechanism of action. Forexample, cholesterol absorption inhibitors inhibit absorption of dietarycholesterol and inhibit reabsorption of biliary cholesterol. Examples ofcholesterol absorption inhibitors include, but are not limited to,phytosterols, ezetimibe, and(3R,4S)-1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)-2-azetidinone (SCH48461). Bile acid sequestrants/resins are polymeric compounds andfunction as ion exchange resins. Bile acid sequestrants exchange anionssuch as chloride ions for bile acids. By doing so, they bind bile acidsand sequester them from enterohepatic circulation. Since bile acidsequesterants are large polymeric structures, they are not well-absorbedfrom the gut into the bloodstream. Thus, bile acid sequestrants, alongwith any bile acids bound to the drug, are excreted via the feces afterpassage through the gastrointestinal tract. Examples of bile acidsequestrants/resins include, but are not limited to cholestyramine,colesevelam, and colestipol. Statins are a class of compounds thatinhibit the enzyme HMG-CoA reductase. Examples of statins include, butare not limited to rosuvastatin, lovastatin, fluvastatin, simvastatin,pravastatin, and atorvastatin. It is believed that niacin and itsderivatives function by stimulating the G-protein coupled receptorGPR109A, which causes the inhibition of fat breakdown in adipose tissue.Examples of niacin and its derivatives include, but are not limited to,niceritrol, niacin, nicofuranose, aluminium nicotinate, nicotinylalcohol, and acipimox. MTP (Microsomal Triglyceride Transfer Protein) isa lipid transfer protein that is required for the assembly and secretionof very low density lipoproteins by the liver and chylomicrons by theintestine. Accordingly, inhibitors of MTP decrease levels of plasmaLDL-C. Examples of MTP inhibitors include, but are not limited to,lomitapide for human use and dirlotapide and mitrapatide for veterinaryuse in dogs. Rodent and human studies suggest that fibrates exert theirhypolipidemic effects via several mechanisms. Examples of fibratesinclude, but are not limited to bezafibrate, ciprofibrate, clofibrate,gemfibrozil, and fenofibrate. CETP (Cholesterylester Transfer Protein)inhibitors improve blood plasma lipid profiles by increasing HDL (“good”cholesterol containing particle) and decreasing LDL (“bad” cholesterolcontaining particle). Examples of CETP inhibitors include, but are notlimited to anacetrapib and evacetrapib.

In addition to the aforementioned disease states, several otherconditions or disorders can also benefit from treatment with thecompositions described herein, such as for example; metabolic syndrome;macular degeneration (AREDS2 Research Group et. al. The Age-Related EyeDisease 2 (AREDS2): study design and baseline characteristics (AREDS2report number 1), Opthalmology. 2012 November 119(11):2282-9. doi10.1016/j.optha 2012.05.027. Epub 2012 Jul. 26; SanGiovanni J P et. al.,ω-3 long-chain polyunsaturated fatty acid intake and 12-y incidence ofneovascular age-related macular degeneration and central geographicatrophy: AREDS report 30, a prospective cohort study from theAge-Related Eye Disease Study. Am. J. Clin. Nutr. 2009; 90:1601-70.);cognitive impairment resulting from surgery or traumatic brain injury,such as for example resulting from a concussion (Lewis M. et. al.Therapeutic use of omega-3 fatty acids in severe head trauma. Am J EmergMed. 2013 January; 31(1):273.e5-8. doi: 10.1016/j.ajem.2012.05.014. Epub2012 Aug. 3; Mills J D. et. al. Dietary supplementation with the omega-3fatty acid docosahexaenoic acid in traumatic brain injury. Neurosurgery.2011 February; 68(2):474-81; discussion 481. doi:10.1227/NEU.0b013e3181ff692b.); major depression, suicide, post-partumdepression (Logan A C. Omega-3 fatty acids and major depression: aprimer for the mental health professional. Lipids Health Dis. 2004 Nov.9; 3:25; Lewis M D et al. Suicide deaths of active-duty US military andomega-3 fatty-acid status: a case-control comparison. J Clin Psychiatry.2011 December; 72(12):1585-90. doi: 10.4088/JCP.11m06879. Epub 2011 Aug.23; Makrides M. et. al. Docosahexaenoic acid and post-partumdepression—is there a link? Asia Pac J Clin Nutr. 2003; 12 Suppl:537.);inflammation (Kelley D S et. al. DHA supplementation decreases serumC-reactive protein and other markers of inflammation inhypertriglyceridemic men. J Nutr. 2009 March; 139(3):495-501. doi:10.3945/jn.108.100354. Epub 2009 Jan. 21.); primary sclerosingcholangitis (Martin C R. et. al. The safety and efficacy of oraldocosahexaenoic acid supplementation for the treatment of primarysclerosing cholangitis—a pilot study. Aliment Pharmacol Ther. 2012January; 35(2):255-65. doi: 10.1111/j.1365-2036.2011.04926.x. Epub 2011Nov. 30.), borderline personality disorder in women (Zanarini M C et al.Omega-3 Fatty acid treatment of women with borderline personalitydisorder: a double-blind, placebo-controlled pilot study. Am JPsychiatry. 2003 January; 160(1):167-9.), breast cancer (Bougnoux P. etal. Improving outcome of chemotherapy of metastatic breast cancer bydocosahexaenoic acid: a phase II trial. Br J Cancer. 2009 Dec. 15;101(12):1978-85. doi: 10.1038/sj.bjc.6605441. Epub 2009 Nov. 17.),non-alcoholic fatty acid liver disease (Parker H M. et. al. Omega-3supplementation and non-alcoholic fatty liver disease: a systematicreview and meta-analysis. J Hepatol. 2012 April; 56(4):944-51. doi:10.1016/j.jhep.2011.08.018. Epub 2011 Oct. 21; Nobili V. Docosahexaenoicacid for the treatment of fatty liver: Randomised controlled trial inchildren. Nutr Metab Cardiovasc Dis. 2012 Dec. 7. pii:S0939-4753(12)00256-6. doi: 10.1016/j.numecd.2012.10.010. [Epub ahead ofprint]; Christopher M. D. et. al. Menhaden oil decreases high-fatdiet-induced markers of hepatic damage, steatosis, inflammation, andfibrosis in obese Ldlr−/− mice. J Nutr. 2012 August; 142(8):1495-503.doi: 10.3945/jn.112.158865. Epub 2012 Jun. 27.), and improvement incognition and behavior in children (Richardson A J. et. al.Docosahexaenoic acid for reading, cognition and behavior in childrenaged 7-9 years: a randomized, controlled trial (the DOLAB Study). PLoSOne. 2012; 7(9):e43909. doi: 10.1371/journal.pone.0043909. Epub 2012Sep. 6.). These conditions or disorders can be treated by administeringthe compositions described herein to a subject, typically a human, inneed of such administration.

Kits

Packaged pharmaceutical kits are included herein. The kits comprisecompositions described herein as unit dosage forms in a container andinstructions for using the dosage form to treat a subject having adisease or disorder responsive to treatment by administration of thedosage forms comprising the compositions described herein.

The packaged pharmaceutical kits provide prescribing information, overthe counter medical use information, and/or nutritional information forthe dosage form including, for example and without limitation, to asubject or health care provider, or as a label in a packagedpharmaceutical kit. Information included in the kit may include, forexample and without limitation, efficacy, dosage and administration,contraindication and adverse reaction information pertaining to theOmega-3 fatty acid dosage form. The dosage and administrationinformation, for example, can include dosing frequency as well asadministration of the compositions with or without food.

In certain embodiments the dosage forms comprising the compositionsprovided herein are in the form of liquid or capsules provided either asblister packages or in bottles together with over the counter medicaluse information and/or nutritional information.

The packaged pharmaceutical kits can comprise one or more of thecompositions described herein as the only active ingredient. In otherembodiments, one or more of the compositions described herein can bepackaged in combination with one or more active agents other than anon-Omega 3 ester, such as for example and without limitation, one ormore other lipid lowering or cholesterol lowering agents selected fromthe group consisting of cholesterol absorption inhibitors, bile acidsequestrants/resins, statins, niacin and derivatives, MTP inhibitors,fibrates and CETP inhibitors.

Dosage Forms

Any of the compositions provided herein comprising at least one Omega-3fatty acid ester can be provided as a pharmaceutical composition, anutraceutical formulation, or a dietary supplement.

The pharmaceutical compositions described herein may further include oneor more pharmaceutically acceptable excipients. Pharmaceuticallyacceptable excipients include, but are not limited to, carriers,preservatives, and/or coloring agents. General considerations in thecomposition and/or manufacture of pharmaceutical compositions may befound, for example, in Remington The Science and Practice of Pharmacy21st ed., Lippincott Williams & Wilkins, 2005.

In certain embodiments, the compositions described herein can beformulated as a liquid for oral administration. Liquid compositionsinclude solutions, suspensions and emulsions. Examples of liquidpharmaceutical preparations include propylene glycol solutions andsolutions containing sweeteners for oral solutions, suspensions andemulsions. When the liquid composition comes into contact with anaqueous medium, such as for example an aqueous medium having an acidicenvironment, the composition forms micelles.

In certain embodiments, the dosage form comprises micelles pre-formedprior to administration to a subject in need of such administration.Such pre-formed micelles are stable at room temperature.

In other embodiments, the compositions described herein can beformulated as a fill material for a soft gelatin capsule. Likewise, whenthe contents of the soft gelatin capsule comes into contact with anaqueous medium, the composition forms micelles upon disintegration ofthe capsule.

A capsule may be prepared, e.g., by placing the compositions describedabove inside a capsule shell. A capsule is a dosage form administered ina special container or enclosure containing an active agent. In someembodiments the compositions described herein can be filled into softcapsules. A capsule shell may be made of methylcellulose,hydroxypropylmethyl cellulose, polyvinyl alcohols, or denatured gelatinsor starch or other material. Hard shell capsules are typically made ofblends of relatively high gel strength bone and pork skin gelatins. Insome embodiments the unit dosage form is a gel capsule. In someembodiments the capsule shell is a glycerin capsule shell, for exampleproduct no. GSU0051 manufactured by SwissCaps and which meets USP 25requirements (SwissCaps, USA 14193 SW 119th Ave., Miami/Fla., U.S.33186). In other embodiments the capsule is a bovine gelatin shell, forexample SwissCaps product no. GSU0708. Other suitable capsule shellmaterials include polyethylene, polypropylene, poly(methylmethacrylate),polyvinylchloride, polystyrene, polyurethanes, polytetrafluoroethylene,nylons, polyformaldehydes, polyesters, cellulose acetate, andnitrocellulose. The capsule shell itself may contain small amounts ofdyes, opaquing agents, plasticizers, and preservatives. Conventionalmethods for preparing other solid dosage forms, for example, capsules,suppositories, and the like are also well known. Gelatin capsule shellsmay be made also be made of tapioca, grass, vegetable derived or fishderived gelatin. For example K-CAPS (Capsuline, Inc. Pompano Beach,Fla.) is a certified Kosher soft capsule shell of vegetable origin.Other vegetarian derived gelatin capsules may, be made of vegetablederived hydroxypropylmethyl cellulose (HPMC). Capsules shells may alsocontain Modified Maize Starch, Glycerol, and Carrageenan as a gellingagent.

In other embodiments the capsule has a shell comprising the material ofthe rate-limiting membrane, including coating materials, and filled withthe compositions described herein. Capsule shells may be made of aporous or a pH-sensitive polymer made by a thermal forming process. Incertain embodiments the capsule shell in the form of an asymmetricmembrane; i.e., a membrane that has a thin skin on one surface and mostof whose thickness is constituted of a highly permeable porous material.

Yet another useful capsule, a “swelling plug device”, can be used. Thecompositions described herein can be incorporated into a non-dissolvingcapsule-half of the device which is sealed at one end by a hydrogelplug. This hydrogel plug swells in an aqueous environment, and, afterswelling for a predetermined time, exits the capsule thus opening a portthrough which the active agent can leave the capsule and be delivered tothe aqueous environment. Preferred hydrogel-plugged capsules are thosewhich exhibit substantially no release of active agent from the dosageform until the dosage form has exited the stomach and has resided in thesmall intestine for about 15 minutes or more, preferably about 30minutes or more, thus assuring that minimal Omega-3 fatty acid ester isreleased in the stomach or the small intestine. Hydrogel-pluggedcapsules of this type have been described in patent applicationWO90/19168.

The dosage forms may contain a plasticizer, particularly in a capsuleshell. Suitable plasticizers include, e.g., polyethylene glycols such asPEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350, and PEG 800, stearicacid, propylene glycol, oleic acid, triethyl cellulose, triacetin,glycerin, sorbitol, sorbitan or combinations thereof.

In additional embodiments, the compositions can be formulated as aliquid for parenteral administration.

Compositions can be formulated as one or more dosage units. In someembodiments, it can be advantageous to formulate oral compositions indosage unit form for ease of administration and uniformity of dosage.Dosage unit forms described in some embodiments can refer to physicallydiscrete units suited as unitary dosages for the subject to be treated;each unit containing a predetermined quantity of active compositioncalculated to produce the desired therapeutic effect in association withthe suitable pharmaceutical carrier. In certain embodiments, the dosageform may optionally contain a flavorant such as orange oil,substantially pure d-limonene, and an antioxidant such as tocopherol,ascorbyl palmitate or a combination of antioxidants.

Functional Foods

In certain embodiments, the compositions described herein comprisemicelles pre-formed prior to administration to a subject in need of suchadministration. Such pre-formed micelles are stable at room temperature.

Accordingly, either such pre-formed micelles or the pre-micellizedcompositions described herein can be added to foods, which can then beconsumed as part of a healthy diet for enriching a subject's Omega-3fatty acid levels or as a dietary treatment in addition to theoral/parenteral administration of the compositions described herein asprescribed by a health professional.

In certain embodiments, the functional food is in the form of edible ordrinkable compositions, e.g., foodstuffs such as chewable or ediblebars, confectionary products (e.g., chocolate bars), cookies, juicedrinks, baked or simulated baked goods (e.g., brownies), biscuits,lozenges or chewing gum. Examples of chewable or edible bars includechocolate bars or energy bars. Such functional foods can be particularlyuseful to people participating in sports or other forms of exercise.

In certain embodiments, the functional foods may also be in the form of,for example, butter, margarine, bread, cake, milk shakes, ice cream,yogurt and other fermented milk product.

In certain embodiments, the functional food can also be in the form of aliquid to be sprayed on meats, salads or other foods.

Other forms of the functional foods can be breakfast cereals, such asfor example, grain flakes, muesli, bran, oatmeal.

When the functional food product is in a drinkable form, thecompositions described herein can be added directly to the drink, suchas for example plain milk, flavored milk, fermented milk products orjuices. The compositions will form micelles comprising the Omega-3 fattyacid esters in the drinkable product.

When the functional food is in the form of a solid edible product, thecompositions described herein can be first added to an aqueous medium,wherein the composition will form micelles as described herein. Theaqueous medium comprising the micelles can subsequently be eithersprayed onto the solid edible product or mixed into the ingredients whenmanufacturing the edible product.

The invention is further defined by reference to the following examples,which are not meant to limit the scope of the present invention. It willbe apparent to those skilled in the art that many modifications, both tothe materials and methods, may be practiced without departing from thepurpose and interest of the invention.

NON-LIMITING WORKING EXAMPLES Example 1

The amounts and percentages of the ingredients comprising one embodimentof the composition, also referred to as SC401, are shown in Table 1:

TABLE 1 COMPOSITION (FILL MASS)/dosage form INGREDIENT Amount (mg) %(wt/wt) Total Omega-3 fatty acid 754.3 68.57 Ethyl Esters EPA EthylEsters 392.2 35.65 DHA Ethyl Esters 165.9 15.08 Polysorbate 80 337.930.72 PLURONIC ® F87 7.8 0.71 GEL MASS/dosage form INGREDIENT Amount(gm) % (wt/wt) Gelatin 270 40 Glycerin 135 20 Purified water 270 40

The manufacturing process for the dosage form comprising one embodimentof the composition can be separated into three stages: a) the processfor manufacturing the composition (fill mass), b) the process formanufacturing the gel mass used for encapsulating the fill mass, and c)the encapsulation process. Stages (a) and (b) can be carried out ineither order.

The process for manufacturing the composition begins by weighingappropriate amounts of the Polysorbate 80 and PLURONIC® F87 as per thedesired batch size and mixing them to homogeneity at 60° C. in astainless steel tank. This mixture is allowed to cool to roomtemperature before the substantially pure Omega-3 fatty acid ethyl estermixture is vacuum-transferred quantitatively into the same stainlesssteel tank containing the Polysorbate 80 and PLURONIC® F87. This mixtureis again mixed to homogeneity at room temperature before being blanketedwith nitrogen. This final composition is also termed the “fill mass”.

The process for manufacturing the gel mass begins by weighingappropriate amounts of each of the glycerin and water as per the desiredbatch size and mixing them to homogeneity in a separate stainless steelmixer at about 80° C. Next, the appropriate amount of gelatin is weighedas per the batch size, added to the glycerin/water mixture and againmixed to homogeneity at 80° C. before being degassed under vacuum. Thisfinal mixture comprising glycerin/water/gelatin is termed the “gelmass”.

Depending on the desired shape of the capsule, suitable dies andtransfer tubing are installed into a soft gel encapsulation apparatus(SS-60 Softgel Encapsulation Machine by SKY Softgel Co. Ltd., Incheon,Korea). The fill mass is pumped into the dies containing a pre-formedribbon comprising the semi-solid gel mass. The dies shape the softgelatin capsules, which are then tumble dried for about 20-60 min. Thecapsules are transferred onto a tray and dried in alow-temperature/humidity drying room and dried until the capsules reachabove 75 shore hardness. The capsules are then inspected, sorted,polished, printed and packaged into bottles. The bottles are affixedwith a label, which includes prescribing information. Alternatively, thebottles can be packaged into boxes with a package insert, which includesprescribing information.

Example 2

Experiments were conducted to determine micelle formation in twocompositions, A and B, as shown in Table 2. Both compositions wereprepared as described in Example 1 comprising Omega-3 fatty acid ethylesters, in which the Omega-3 fatty acid ethyl esters had increasedabsorption and the food effect was substantially eliminated.

TABLE 2 % (wt/wt) Ingredients Composition A Composition B Omega-3 fattyacid Ethyl Esters 68.57 75.0 Polysorbate 80, NF 30.71 20.0 PLURONIC ®F87 0.71 5.0 Combined surfactant HLB 15.3 16.8 Whole Product HLB 13 13.2

The compositions which formed well dispersed micelles generally had acombined surfactant HLB value of about 15 to about 17.

Other compositions with Polysorbate 80 levels between 27-29% incombination with PLURONIC® F87 between about 7% to about 22% generallyformed large oil globules. These compositions had a combined surfactantHLB value of from about 17 to about 19. Based on these experiments thewhole product HLB was from about 13 and about 14.4 and the combinedsurfactant HLB was between about 12 to about 17.

Example 3

Compositions A and B (1,000 mg), as shown in Table 2, were added toseparate containers containing 500-900 mL of water in 0.1N HCl, underUnited States Pharmacopeia (USP) dissolution 2 conditions, as describedin General Chapter 711, United States Pharmacopeia, 34/National/2011,and observed. Neither composition was subjected to any agitation orshearing. When observed under the microscope, very small, well dispersedmicelles were visible. The micelles were stable for over twelve monthsat room temperature and there was no apparent separation of the Omega-3fatty acid esters from the other ingredients of the composition. Thus,compositions that included Polysorbate 80 levels between 20-31% incombination with PLURONIC® F87 at 0.7 to 5% formed stable micelles.

Example 4

A human subject ingested composition A in Example 2 (the “ExperimentalComposition”) and underwent blood monitoring to measure the increase inabsorption of the Omega-3 fatty acid ethyl esters compared to theOmega-3 fatty acid ethyl esters in an Omega-3 fatty acid ethyl estercomposition that is representative of currently marketed drug andnutritional Omega-3 products (the “Standard Composition”). The StandardComposition was manufactured by encapsulating Omega-3 ethyl esters usingstandard encapsulating methods. Absorption of Omega-3 fatty acid ethylesters was determined by comparing changes in subject's OmegaIndexfollowing ingestion of the compositions, as measured using theOmegaIndex test kit by OmegaQuant. Prior to ingestion of a composition,blood was drawn from the subject to determine subject's baselineOmegaIndex. The subject then ingested soft gel capsules containingeither the Experimental Composition or the Standard Composition. Asubsequent blood draw occurred at four hours post-ingestion. The subjectremained in the fasted state from the initial baseline blood drawthrough the four-hour blood draw. The results are shown in Table 4.

TABLE 4 Dose EPA + DHA Omega Index Capsule Composition Ethyl EstersInitial 4 hour Increase Standard Composition 1.52 g 5.2 5.3 1.92%Experimental Composition 1.46 g 5.4 5.7 5.55% Dose A (4 capsules, 400 mgtotal fill weight per capsule) Experimental Composition 3.65 g 4.9 5.38.16% Dose B (10 capsules, 400 mg total fill weight per capsule)

Example 5

An Open-label, Randomized, 3 arm, Parallel group, Proof of Concept Studywas conducted to evaluate the serum TG lowering efficacy and safety ofSC401 Capsules 1100 mg (manufactured as described in Example 1) vs.LOVAZA® (Omega-3-acid ethyl esters) Capsules 1000 mg vs. PLACEBO inhypertriglyceridemic subjects with serum TG between 250 and 500 mg/dLwhen dosed under fasting conditions.

The aim of this study was to evaluate the effectiveness of SC401 vs.LOVAZA® vs. Placebo on TG reduction over 14 days of treatment. 45subjects were enrolled in the study in order to complete at least 12subjects in each of the three treatment arms.

The following inclusion and exclusion criteria were used to select thesubjects for this study:

Inclusion Criteria:

-   -   Men and women 18 years of age or older.    -   Serum TG between 200 and 500 mg/dL.    -   Normally active and in good health on the basis of medical        history, brief physical examination, electrocardiogram, and        routine laboratory tests.    -   Be neither over weight nor under weight for his/her height as        per the attached height/weight table values (see attached        height/weight table).    -   Provide written informed consent.    -   If female and of child bearing potential; is practicing an        acceptable method of birth control for the duration of the study        as judged by the investigator (s), such as condoms, foams,        jellies, diaphragm, intrauterine device (IUD), or abstinence; or        is postmenopausal for at least 1 year; or is surgically sterile        (bilateral tubal ligation, bilateral oophorectomy, or        hysterectomy).

Exclusion Criteria:

-   -   Severe hypertriglyceridemia (serum TG>500 mg/dL).    -   Intolerance to Omega-3 or fish.    -   Use of Omega-3 fish oil, other EPA or DHA and/or DHA fortified        foods or other TG lowering medications within three months of        study drug initial administration, or during the study.    -   Consumption of any fish within seven days of study drug initial        administration or during the study.    -   Recent history of certain heart, kidney, liver, lung, or        gastrointestinal diseases or cancer (except non-melanoma skin        cancer).    -   Diabetes or receiving insulin therapy.    -   Pregnant or lactating females. Women of childbearing potential        who are not using a medically approved method of contraception.    -   Use of certain types of hormones, anticonvulsant drugs,        immunologic drugs, antibiotic, antifungal and antiviral drugs,        and cardiac drugs.    -   Use of warfarin (Coumadin).    -   Recent history (past 12 month) of drug abuse or alcohol abuse.    -   Exposure to any investigational product, within 28 days prior to        study drug administration.    -   Subjects diagnosed with the following conditions:        -   Endocrine diabetes mellitus, hypothyroidism, pregnancy;        -   Nutritional obesity, alcohol access;        -   Renal nephrotic disease, chronic renal failure;        -   Hepatic disease cholestas, hepatocellular dysfunction;        -   Immunoglobulin excess paraproteinemia;        -   Gout;        -   Any other condition the investigator believes would            interfere with the patient's ability to provide informed            consent, comply with study instructions, or which might            confound the interpretation of the study results or put the            patient at undue risk; and subjects on the following            medications Thiazide diuretic, Steroid hormones, Microsomal            enzyme, Retinoic acid derivatives, Protease inhibitors (HIV            infection).

The Informed Consent Document (ICD) was read by the volunteer and signedprior to study specific procedures. Additionally, the following testswere be performed at clinic entry for each period

-   -   Urine screen for drugs of abuse—including cocaine, cannabis,        amphetamines, barbiturates, benzodiazepines and opiates.        Subjects were rejected/withdrawn from the study if the result        was positive for these drugs,    -   Alcohol breath test—subjects were rejected/withdrawn from the        study if the result was positive for alcohol,    -   Urine pregnancy test (HCG) (for female subjects only)—Female        subjects were rejected/withdrawn from the study if result was        positive for pregnancy, and    -   Gynecological & breast examination (for female subjects        only)—subjects were rejected/withdrawn from the study if there        were any abnormalities in the examination.

Subjects were housed in the clinical facility from at least 48 hourspre-dose to at least 14 days and were requested to stay for 16consecutive nights in the facility.

Subjects were fasted for at least 10 hours before morning dosing andwere instructed to abstain from consuming caffeine and/or xanthinecontaining products (i.e. coffee, tea, chocolate, andcaffeine-containing sodas, colas, etc.), alcohol and vitaminsupplements, including vitamin C and ascorbic acid and grapefruit andits juice, for at least 48 hours prior to dosing and throughout thestudy. No citrus juices, including orange juice and grapefruit juice,were provided during the study.

After overnight fast of 10 hours subjects were dosed under monochromaticlight or low light condition as follows:

SC401 (Omega-3 Fatty Acid Ethyl Esters, 1100 mg) 2 capsules (as singledose), taken upon awakening (at least 2 hours before breakfast takenwith water only on an empty stomach); then 2 capsules (as single dose)taken at bedtime (at least 2 hours after dinner taken with water onlyand no food or liquids thereafter for the night), or

LOVAZA® (Omega-3 Fatty Acid Ethyl Esters, 1000 mg, of GlaxoSmithKline,RTP, NC 2770) 2 capsules (as single dose) taken upon awakening (at least2 hour before breakfast taken with water only on an empty stomach); then2 capsules (as single dose) taken at bedtime (at least 2 hours afterdinner taken with water only and no food or liquids thereafter for thenight), or

PLACEBO (Ethyl Oleate, 1000 mg capsules) 2 capsules (as single dose)taken upon awakening (at least 2 hour before breakfast taken with wateronly on an empty stomach); then 2 capsules (as single dose) taken atbedtime (at least 2 hours after dinner taken with water only and no foodor liquids thereafter for the night).

The amounts of Omega-3 fatty acid ethyl esters comprising LOVAZA®, SC401and the placebo are shown in the Table 5 below:

TABLE 5 Capsule Fill Composition (mg) SC401 LOVAZA ® Placebo TotalOmega-3 Fatty Acid 754 934 0 Ethyl Esters EPA Ethyl Esters 362 482 0 DHAEthyl Esters 166 370 0 Polysorbate 80, NF 338 0 0 PLURONIC ® F87 7.8 0 0Ethyl Oleate 0 0 1000

4 blood samples (8 mL each) were collected over the study period. Theblood samples will be collected at T_(s), T₀, T_(7d), T_(14d) in plainvacuum tubes by direct vein puncture. Vacutainers were placed upright ina rack kept in wet ice bath until transferred to Diagnostic department.

Clinical laboratory tests performed were performed on the collectedsamples. Details of the tests performed are listed below.

T_(s) & T_(14d): Fasting liver ALT & AST levels and fastingtriglyceride, HDL, LDL, total cholesterol.

T₀ & T_(7d): Fasting triglyceride, HDL, LDL & total cholesterol levels.

Statistical analyses were performed on the data obtained from thetriglycerides levels of patients who completed the study.

Each capsule of SC401 contained 362 mg of EPA and 166 mg of DHA(total=528 mg) whereas each capsule of LOVAZA® contained 482 mg of EPAand 370 mg of DHA (total=852 mg). Thus, the total dose of SC401 was 0.62that of the dose provide by LOVAZA®. To equalize the doses betweengroups, the doses were adjusted.

The dose adjusted results are shown below for each parameter in Tables6-11.

TABLE 6 Summary statistics for triglyceride levels (with dose adjustedfor Treatment SC401, LOVAZA ® & Placebo) Parameters SC401 LOVAZA ®Placebo N 14 15 15 Baseline values 291.3 ± 43.65 310.8 ± 35.57 332.9 ±37.39 Day 7 261.1 ± 82.29 214.8 ± 45.56 258.9 ± 90.13 Day 14 203.6 ±86.10 219.4 ± 76.81 240.8 ± 74.75 Change from  −30.0 ± 101.79 −96.0 ±52.54  −74.0 ± 101.99 baseline on day 7 Percent −11.9 ± 52.61 −30.3 ±16.39 −21.3 ± 28.88 change on day 7 Change from −87.6 ± 89.19 −91.4 ±76.62 −92.1 ± 68.86 baseline on day 14 Percentage −48.6 ± 51.55 −29.2 ±23.81 −27.9 ± 21.10 change on day 14

TABLE 7 Statistical comparison of change from baseline values ofTriglyceride levels after dose adjustment for SC401 Parameters SC401LOVAZA ® Placebo N 14 15 15 Baseline values 469.6 ± 70.41 310.8 ± 35.57332.9 ± 37.39 Change from −48.4 ± 43.88 −96.0 ± 13.57 −74.0 ± 26.33baseline on (0.2901) (<0.0001) (0.0139) day 7(p-value)* Change from−141.2 ± 38.45  −91.4 ± 76.62 −92.1 ± 17.78 baseline on (0.0028) (0.0004) (0.0001) day 14(p- value)* *Values are mean change ± Standarderror

After dose adjustment, the percent change from baseline in triglyceridelevels in the SC401 treatment group was −48.6±51.55 compared to−29.2±23.81 in the LOVAZA® group and −27.9±21.10 in the placebo group.The differences in Triglyceride values were not significantly differentbetween treatments (SC401, LOVAZA® and Placebo). The reduction intriglyceride levels did not differ significantly when the SC401b werecompared with LOVAZA® and Placebo with respect to day 7 as well as day14.

TABLE 7 Summary statistics for LDL levels (with dose adjusted forTreatment SC401, LOVAZA ® & Placebo) Parameters SC401b LOVAZA ® PlaceboN 5 7 10 Baseline values 84.6 ± 25.94 72.9 ± 25.72 73.0 ± 25.98 Day 7103.2 ± 42.60  86.4 ± 34.82 108.2 ± 34.90  Day 14 153.6 ± 28.93  150.1 ±38.85  106.5 ± 16.93  Change from 18.6 ± 33.92 13.5 ± 44.79 35.2 ± 32.08baseline on day 7 Percent 25.2 ± 40.46 28.3 ± 57.46 58.0 ± 55.20 changeon day 7 Change from 69.0 ± 51.61 77.2 ± 47.26 33.5 ± 35.13 baseline onday 14 Percent 103.2 ± 89.08  123.4 ± 70.41  64.8 ± 68.90 change on day14

Fewer observations were observed with matching baseline and day 7, day14 values for the three treatments. The above table shows thesignificant increase from the baseline in all the treatments.

TABLE 8 Statistical comparison of change from baseline values of LDLlevels Parameters SC401 LOVAZA ® Placebo N 5 7 10 Baseline values 84.6 ±25.94 72.9 ± 25.72 73.0 ± 25.98 Change from 18.6 ± 15.17 13.5 ± 16.9335.2 ± 10.14 baseline on (0.2874) (0.4556) (0.0070) day 7(p- value)*Change from 69.0 ± 23.08 77.2 ± 17.86 33.5 ± 11.11 baseline on (0.0404)(0.0050) (0.0145) day 14(p- value)* *Values are mean change ± Standarderror.

The change (increase) from baseline LDL values were statisticallysignificant for all treatments at day 14(p<0.05).

The increase in LDL values did not differ significantly between SC401and LOVAZA® as well as SC401 Vs Placebo. A statistically significantincrease was observed with LOVAZA® and Placebo.

TABLE 9 Summary statistics for HDL levels (with dose adjusted forTreatment SC401, LOVAZA ® & Placebo) Parameters SC401 LOVAZA ® Placebo N5 7 10 Baseline values 41.2 ± 6.18 40.1 ± 7.64  41.8 ± 4.54  Day 7 43.8± 8.41 44.7 ± 10.90 46.6 ± 6.22  Day 14 42.6 ± 7.96 47.0 ± 3.74  44.2 ±8.89  Change from  2.6 ± 6.11 4.6 ± 6.61 4.9 ± 7.14 baseline on day 7Percent  6.4 ± 17.17 12.0 ± 15.05 12.4 ± 18.47 change on day 7 Changefrom  1.4 ± 13.99 6.9 ± 6.75 2.5 ± 7.40 baseline on day 14 Percent  8.0± 33.01 20.3 ± 21.08  5.8 ± 17.27 change on day 14

The summary table for HDL reveals that there is an increase of HDLvalues from baseline.

TABLE 10 Statistical comparison of change from baseline values of HDLlevels Parameters SC401 LOVAZA ® Placebo N 5 7 10 Baseline values 41.2 ±6.18  40.1 ± 7.64  41.8 ± 4.54  Change from 2.6 ± 2.73 4.6 ± 2.50 4.9 ±2.26 baseline on (0.3950) (0.1171) (0.0603) day 7(p-value)* Change from1.4 ± 6.23 6.9 ± 2.55 2.5 ± 2.34 baseline on (0.8339) (0.0362) (0.3226)day 14(p- value)* *Values are mean change ± Standard error.

The increase in HDL values from baseline is significant at Day 14 fortreatment LOVAZA® and no statistically significant increase was observedfor treatments SC401 and Placebo from baseline.

TABLE 11 Comparison of the mean change between treatments of HDL levelsComparison SC401 Vs SC401 Vs LOVAZA ® Vs LOVAZA ® Placebo Placebo Changefrom 0.6246 0.5511 0.9343 baseline on day 7 Change from 0.3151 0.83420.3 baseline on day 14

The change from baseline (increase) was comparable between treatmentSC401 and LOVAZA® as well as SC401 and Placebo.

Based on the statistical results obtained, after dose adjustment, thepercent change from baseline in triglyceride levels in the SC401treatment group was −48.6±51.55 compared to −29.2±23.81 in the LOVAZA®group and −27.9±21.10 in the placebo group. The differences intriglyceride values were not significantly different between treatments(SC401, LOVAZA®, Placebo). Thus it can be inferred that the twotreatments (SC401b and LOVAZA®) behave in a similar manner with respectto change in triglyceride values in patients with highhypertriglyceridemia between 200 and 499 mg/dL under fasting conditions.

No adverse effects were observed in any treatment group. SC401 was safeand well tolerated.

Example 6

An open-label, balanced, randomized, 2-arm, parallel group, Proof ofConcept study was conducted to evaluate the serum TG lowering efficacyand safety of SC401 Capsules 1100 mg (manufactured as described inExample 1) vs. Placebo (Corn Oil) in patients with hypertriglyceridemiabetween 250 and 500 mg/dL under fasting conditions.

The main purpose of this study was to evaluate the effectiveness ofSC401 vs Placebo (Corn Oil) on TG reduction over 28 days of treatment.36 patients were enrolled in the study in order to complete at least 15patients in each treatment arm.

The following inclusion and exclusion criteria were used to select thesubjects for this study:

Inclusion Criteria:

-   -   Men and women 18 years of age or older.    -   Serum TG levels between 300 and 500 mg/dL.    -   Normally active and in good health on the basis of medical        history, brief physical examination, electrocardiogram, and        routine laboratory tests.    -   Provide written informed consent.    -   If female and of child bearing potential; is practicing an        acceptable method of birth control for the duration of the study        as judged by the investigator (s), such as condoms, foams,        jellies, diaphragm, intrauterine device (IUD), or abstinence; or        is postmenopausal for at least 1 year; or is surgically sterile        (bilateral tubal ligation, bilateral oophorectomy, or        hysterectomy).

Exclusion Criteria:

-   -   Severe hypertriglyceridemia (serum TG>500 mg/dL).    -   Intolerance to Omega-3 or fish.    -   Use of Omega-3 fish oil, other EPA or DHA and/or DHA fortified        foods or other TG lowering medications within three months of        study drug initial administration, or during the study.    -   Consumption of any fish within seven days of study drug initial        administration or during the study.    -   Recent history of certain heart, kidney, liver, lung, or        gastrointestinal diseases or cancer (except non-melanoma skin        cancer).    -   Diabetes or receiving insulin therapy.    -   Pregnant or lactating females. Women of childbearing potential        who are not using a medically approved method of contraception.    -   Use of certain types of hormones, anticonvulsant drugs,        immunologic drugs, antibiotic, antifungal and antiviral drugs,        and cardiac drugs.    -   Use of warfarin (Coumadin).    -   Recent history (past 12 month) of drug abuse or alcohol abuse.    -   Exposure to any investigational product, within 28 days prior to        study drug administration.    -   Subjects diagnosed with the following conditions:        -   Endocrine diabetes mellitus, hypothyroidism, pregnancy;        -   Nutritional obesity, alcohol access;        -   Renal nephrotic disease, chronic renal failure;        -   Hepatic disease cholestas, hepatocellular dysfunction;        -   Immunoglobulin excess paraproteinemia;        -   Gout;        -   Any other condition the investigator believes would            interfere with the patient's ability to provide informed            consent, comply with study instructions, or which might            confound the interpretation of the study results or put the            patient at undue risk; and subjects on the following            medications Thiazide diuretic, Steroid hormones, Microsomal            enzyme, Retinoic acid derivatives, Protease inhibitors (HIV            infection).

The Informed Consent Document (ICD) was read by the volunteer and signedprior to study specific procedures. Additionally, the following testswere be performed at clinic entry for each period:

-   -   Urine screen for drugs of abuse—including cocaine, cannabis,        amphetamines, barbiturates, benzodiazepines and opiates.        Subjects were rejected/withdrawn from the study if the result        was positive for these drugs,    -   Alcohol breath test—subjects were rejected/withdrawn from the        study if the result was positive for alcohol,    -   Urine pregnancy test (HCG) (for female subjects only)—Female        subjects were rejected/withdrawn from the study if result was        positive for pregnancy, and    -   Gynecological & breast examination (for female subjects        only)—subjects were rejected/withdrawn from the study if there        were any abnormalities in the examination.

Subjects were housed in the clinical facility from at least 60 hourspre-dose to at least 29 days and were requested to stay for 31consecutive nights in the facility.

Subjects were fasted for at least 10.00 hours before morning dosing.Subjects were instructed to abstain from consuming caffeine and/orxanthine containing products (i.e. coffee, tea, chocolate, andcaffeine-containing sodas, colas, etc.), alcohol and vitamin supplementsincluding vitamin C and ascorbic acid and grapefruit and its juice forat least 48.00 hours prior to dosing and throughout the study. No citrusjuices including orange juice and grapefruit juice were provided duringthe study. Subjects were also instructed not to take any prescriptionmedications within 14 days prior to study check in and throughout thestudy. In addition, subjects were instructed not to take any OTCproducts, herbal medications, etc. within 07 days prior to study checkin and throughout the study.

After overnight fast of 10 hours subjects were dosed under monochromaticlight or low light condition as follows:

(1) SC401 3 capsules (as single dose) taken upon awakening (at least 2hours before breakfast taken with water only on an empty stomach); then3 capsules (as single dose) taken at bedtime (at least 2 hours afterdinner taken with water only and no food or liquids thereafter for thenight) or

(2) PLACEBO (Corn Oil) 3 capsules (as single dose) taken upon awakening(at least 2 hour before breakfast taken with water only on an emptystomach); then 3 capsules (as single dose) taken at bedtime (at least 2hours after dinner taken with water only and no food or liquidsthereafter for the night).

Capsules were administered with 240 mL of water at ambient temperaturein sitting posture under the supervision of trained study personnelincluding auditor(s) from the quality assurance department.

The composition of SC401 used in this study is shown in Table 5. Each1100 mg capsule of corn oil placebo comprised 110 mg Palmitic acid, 649mg Linoleic acid and 341 mg Oleic acid.

6 blood samples (4 mL each) were collected over the study period. Theblood samples will be collected at T_(s), T₀, T_(7d), T_(14d) in plainvacuum tubes by direct vein puncture. Vacutainers were placed upright ina rack kept in wet ice bath until transferred to Diagnostic department.

For T_(s), T₀, T_(7d), T_(14d), fasting triglyceride/HDL/LDL/totalcholesterol/non-HDL/Attorney levels for each patient in each of twogroups was determined. Fasting liver ALT/AST (alanineaminotransferase/aspartate aminotransferase) levels for each patient ineach of two groups was also determined at T_(s), T_(14d), T_(21d) andT_(28d).

The data are tabulated in Table 11 to 20 below:

TABLE 11 Summary statistics for triglyceride levels (for Treatment SC401and Placebo): Time Mean ± SD points SC401 Placebo T_(s) 323.7333 ±70.7899 349.5333 ± 62.6177 T_(0 d) 294.6000 ± 15.8421 303.1333 ± 37.6921T_(b) 309.1667 ± 38.6960 326.3333 ± 40.4058 T_(7 d)  269.3333 ± 110.4521312.1333 ± 94.7492 T_(14 d) 169.8667 ± 75.0903 241.3333 ± 63.7939T_(21 d) 162.2000 ± 72.7169 255.4667 ± 86.2619 T_(28 d) 176.8000 ±63.4476  275.2000 ± 152.7146

TABLE 12 Statistical comparison of Triglyceride levels within SC401,Placebo-Corn oil and between SC401 and Placebo-Corn oil: TriglyceridesEfficacy A (Test- SC401B) B (Placebo-Corn oil) endpoint Mean % changeMean % change A vs. B Time Points P-value from baseline(T_(b)) P-valuefrom baseline(T_(b)) P-value T_(7 d) 0.3028 (>0.05) −12.88↓ 0.7197(>0.05) −4.35↓ 0.4136 (>0.05) T_(14 d) 0.0003 (<0.05) −45.06↓ 0.0009(<0.05) −26.05↓ 0.0105 (<0.05) T_(21 d) 0.0002 (<0.05) −47.54↓ 0.0181(<0.05) −21.72↓ 0.0188 (<0.05) T_(28 d) 0.0002 (<0.05) −42.81↓ 0.0730(>0.05) −15.67↓ 0.0610 (>0.05) Where T_(b) = (T_(S) + T₀)/2, consideredas baseline for statistical analysis, T_(S) = Screening day, T_(0 d) =1^(st) day, T_(7 d) = 7^(th) day, T_(14 d) = 14^(th) day, T_(21 d) =21^(st) day, T_(28 d) = 28^(th) day.

The results showed a significant reduction in triglyceride levels in theSC401 group at each time period compared with baseline values. Thereductions of triglyceride levels in the corn oil group were about halfof those seen in the SC401 group. The reduction in triglyceride levelsin the placebo group may have been related to a shift to a controlleddiet that was relatively low in fat. At T_(14d) and T_(21d), differencesin triglyceride levels between the SC401 and placebo groups werestatistically significant.

TABLE 13 Summary statistics for LDL levels for treatment SC401 andPlacebo: Time Mean ± SD points SC401 Placebo T_(s) 110.0667 ± 40.3493114.2000 ± 42.8739 T_(0 d) 131.6667 ± 35.9795 111.0667 ± 23.0975 T_(b)120.8667 ± 28.2846 112.6333 ± 27.2590 T_(7 d) 117.8000 ± 39.3105116.5333 ± 39.6698 T_(14 d) 145.2667 ± 31.2078 123.9333 ± 29.9272T_(21 d) 151.4667 ± 37.0210 117.2000 ± 39.2414 T_(28 d) 152.9333 ±39.9955 124.4286 ± 26.0612

TABLE 14 Statistical comparison of LDL levels within SC401, Placebo-Corn oil and between SC401 and Placebo-Corn oil): LDL Efficacy SC401Placebo-Corn oil SC401 Vs. endpoint Mean % change Mean % change PlaceboTime Points P-value from baseline(T_(b)) P-value from baseline(T_(b))P-value T_(7 d) 0.8947 (>0.05) −2.54↓ 0.4129 (>0.05) 3.46↑ 0.5441(>0.05) T_(14 d) 0.0045 (<0.05) 20.19↑ 0.1024 (>0.05) 10.03↑ 0.5745(>0.05) T_(21 d) 0.0041 (<0.05) 25.32↑ 0.3220 (>0.05) 4.05↑ 0.1638(>0.05) T_(28 d) 0.0020 (<0.05) 26.53↑ 0.0583 (>0.05) 10.47↑ 0.4252(>0.05) Where T_(b) = (T_(S) + T₀)/2, considered as baseline forstatistical analysis, T_(S) = Screening day, T₀ = 1^(st) day, T_(7 d) =7^(th) day, T_(14 d) = 14^(th) day, T_(21 d) = 21^(st) day, T_(28 d) =28^(th) day.

LDL levels in both treatment groups tended to increase. Compared tobaseline values, the percent differences in LDL levels werestatistically significant in the SC401B groups at T_(14d), T_(21d), andT_(28d).

TABLE 15 Summary statistics for HDL levels treatment SC401 and Placebo:Time Mean ± SD points SC401 Placebo T_(s) 36.8000 ± 7.6830  33.8667 ±8.5429  T_(0 d) 41.7333 ± 6.8292  33.9333 ± 7.5068  T_(b) 39.2667 ±5.8580  33.9000 ± 6.8900  T_(7 d) 38.2000 ± 10.5911 35.7333 ± 11.3356T_(14 d) 41.3333 ± 10.1676 41.4000 ± 13.3780 T_(21 d) 40.7333 ± 12.612237.8667 ± 13.7418 T_(28 d) 42.9333 ± 13.8794 42.0000 ± 15.8835

TABLE 16 Statistical comparison of HDL levels within SC401, Placebo-Corn oil and between SC401 and Placebo-Corn oil: HDL Efficacy SC401Placebo-Corn oil SC401 Vs. endpoint Mean % change Mean % change PlaceboTime Points P-value from baseline(T_(b)) P-value from baseline(T_(b))P-value T_(7 d) 0.5614 (>0.05) −2.72↓ 0.4887 (>0.05) 5.41↑ 0.4613(>0.05) T_(14 d) 0.4212 (>0.05) 5.26↑ 0.0009 (<0.05) 22.12↑ 0.0815(>0.05) T_(21 d) 0.8583 (>0.05) 3.74↑ 0.7615 (>0.05) 11.70↑ 0.6516(>0.05) T_(28 d) 0.3303 (>0.05) 9.34↑ 0.0256 (<0.05) 23.89↑ 0.3909(>0.05) Where T_(b) = (T_(S) + T₀)/2, considered as baseline forstatistical analysis, T_(S) = Screening day, T₀ = 1^(st) day, T_(7 d) =7^(th) day, T_(14 d) = 14^(th) day, T_(21 d) = 21^(st) day, T_(28 d) =28^(th) day.

The HDL level increased in the SC401 group as well as in the corn oilgroup at each time point. However, for most time points, the increasesfrom baseline were not statistically significant.

TABLE 17 Summary statistics for ALT(SGPT) levels for treatment SC401 andPlacebo: Time Mean ± SD points SC401B Placebo T_(s) 41.2667 ± 30.131848.1333 ± 36.8333 T_(0 d) 63.3333 ± 43.7569 36.6000 ± 12.4028 T_(b)52.3000 ± 33.1511 42.3667 ± 19.3783 T_(7 d) 49.4000 ± 28.6277 54.4667 ±35.0364 T_(14 d) 52.2667 ± 55.8153 46.7333 ± 27.3613 T_(21 d) 49.0000 ±40.4836 39.6667 ± 13.6521 T_(28 d) 46.7857 ± 38.0590 43.6000 ± 15.3707

TABLE 18 Statistical comparison of ALT(SGPT) levels within SC401B,Placebo- Corn oil and between test- SC401 and Placebo-Corn oil:ALT(SGPT) Efficacy SC401 Placebo-Corn oil SC401 Vs. endpoint Mean %change Mean % change Placebo Time Points P-value from baseline(T_(b))P-value from baseline(T_(b)) P-value T_(7 d) 0.6788 (>0.05) −5.54↓0.2293 (>0.05) 28.56↑ 0.5122 (>0.05) T_(14 d) 0.9780 (>0.05) −0.06↓0.4543 (>0.05) 10.31↑ 0.5387 (>0.05) T_(21 d) 0.7609 (>0.05) −6.31↓0.5995 (>0.05) −6.37↓ 0.6816 (>0.05) T_(28 d) 0.7609 (>0.05) −10.54↓0.3028 (>0.05) 2.91↑ 0.3786 (>0.05) Where T_(b) = (T_(S) + T₀)/2,considered as baseline for statistical analysis, T_(S) = Screening day,T₀ = 1^(st) day, T_(7 d) = 7^(th) day, T_(14 d) = 14^(th) day, T_(21 d)= 21^(st) day, T_(28 d) = 28^(th) day.

The SGPT level was reduced in SC401 group while it tended to increase incorn oil group. However, these changes were not statisticallysignificant.

TABLE 19 Summary statistics for AST (SGOT) levels for treatment SC401and Placebo: Time Mean ± SD points SC401 Placebo T_(s) 38.8000 ± 23.619631.3333 ± 18.8326 T_(0 d) 46.2000 ± 30.4448 26.9333 ± 5.8733  T_(b)42.5000 ± 23.2048 29.1333 ± 10.3120 T_(7 d) 41.7143 ± 23.9693 40.5333 ±37.9847 T_(14 d) 43.6000 ± 39.6949 51.7333 ± 45.6735 T_(21 d) 35.2000 ±28.2114 30.0000 ± 10.6503 T_(28 d) 32.0667 ± 14.6261 30.7333 ± 7.8510 

TABLE 20 Statistical comparison of AST (SGOT) levels within SC401,Placebo-Corn oil and between SC401 and Placebo-Corn oil: AST (SGOT)Efficacy SC401 Placebo-Corn oil SC401 Vs. endpoint Mean % change Mean %change Placebo Time Points P-value from baseline(T_(b)) P-value frombaseline(T_(b)) P-value T_(7 d) 0.6257 (>0.05) −1.85↓ 0.1876 (>0.05)39.13↑ 0.5043 (>0.05) T_(14 d) 0.3303 (>0.05) 2.59↑ 0.4143 (>0.05)77.57↑ 0.0274 (<0.05) T_(21 d) 0.3303 (>0.05) −17.18↓ 0.7615 (>0.05)2.97↑ 0.1258 (>0.05) T_(28 d) 0.3028 (>0.05) −24.55↓ 0.8904 (>0.05)5.49↑ 0.1516 (>0.05) Where T_(b) = (T_(S) + T₀)/2, considered asbaseline for statistical analysis, T_(S) = Screening day, T₀ = 1^(st)day, T_(7 d) = 7^(th) day, T_(14 d) = 14^(th) day, T_(21 d) = 21^(st)day, T_(28 d) = 28^(th) day.

The SGOT level was reduced in Test-A (SC401B) group while it wasincreased in corn oil group. However, these changes were notstatistically significant.

No adverse effects were observed in both treatment groups in this study.Hence SC401 was concluded to be safe and well tolerated in theparticipated subjects.

The results indicated that SC401 significantly decreased triglyceridelevels from baseline values. There were no statistically significantchanges in HDL, LDL, SGPT and SGOT levels.

In conclusion, SC401 produced a significant decrease in triglyceridelevels in patients with hypertriglyceridemia. Compared with the corn oilplacebo, SC401 was more efficacious in lowering triglycerides levels inpatients with hypertriglyceridemia between 250 and 500 mg/dL underfasting conditions.

Example 7

This study was designed to evaluate whether SC401, manufactured asdescribed in Example 1, is bioavailable under both fed and fastingconditions.

The effects of both fasting and consumption of a high-fat/high-caloriemeal on the bioavailability of EPA and DHA from a single 6-g dose ofSC401 (2,172 mg of EPA+996 mg of DHA=3,168 mg ethyl ester (EE) ofEPA+DHA) was investigated. The dose of SC401 used in the fed and fastedbioavailability studies was slightly lower than that recommended forLOVAZA® (4 g providing 3,360 mg EE of EPA+DHA) to treat high TG.

To eliminate any potential carryover effects associated with a washoutperiod using a crossover design, two separate and independent,open-label, single treatment, single period, single-dose, oralbioavailability studies in healthy, adult men (n=30 each) under fastingand fed conditions were conducted. The studies required a 6-dayin-clinic hospital stay during which prepared meals with controlled fatcontent and calories were provided. Blood samples were collected atspecified time points for pharmacokinetic (PK) evaluation of EPA andDHA. The PK analyses used baseline-adjusted EPA and DHA, total lipids,FFA, and EE in plasma in the fed state and baseline-adjusted EPA and DHAtotal lipids and FFA in plasma in the fasted state. Methods forbioavailability studies described in the FDA's “Draft Guidance onOmega-3-Acid Ethyl Esters” were followed. FDA (2012) Draft Guidance onOmega-3-Acid Ethyl Esters. Although the FDA guidance is specificallydesigned to provide methods to evaluate the equivalence of an activepharmaceutical ingredient (API) vs. a reference drug, the guidance wasused because the agency has described the most effective procedures tobe used to evaluate PK of the EE forms of EPA and DHA in the body.

The purpose of the study, the procedures required, and the length of thehospital stay, were explained to the volunteers prior to the start ofthe study. Volunteers were asked to read the informed consent document,which was followed by a detailed oral presentation provided by themedical personnel at the clinical site. Written informed consent wasobtained from volunteers who fulfilled the inclusion and exclusioncriteria described below. Written informed consent was obtained fromeach volunteer prior to screening and enrollment in the study.

The two studies were separate, independent, open-label, singletreatment, single period, single-dose, oral bioavailability studies inhealthy, adult men (n=30 each) under fed and fasting conditions.Subjects recruited for the fed study were not allowed to participate inthe fasting study.

All enrolled subjects in both studies were housed in the clinicalfacility for at least 60 hours prior to dosing to 48 hours post dosing.Meals were served at pre-specified regular intervals at −59, −48, −44,−39, −35, −24, −20, −15, and −11 hours before dosing and 4, 9, 13, 25,29, 33 and 37 hours after dosing. A standard/controlled diet with no EPAand DHA (˜22% fat) was provided. Water was restricted from 1 hour priorto dosing to 1 hour post dosing. Free access to water was allowed afterhour post dosing.

In the trial conducted under fasting conditions, after an overnightfasting of at least 10 hours, a single oral dose of SC401 wasadministered with about 240 mL of water at ambient temperature to eachsubject in sitting position, under the supervision of the investigatorand trained study personnel. No breakfast was provided.

In the trial conducted under fed conditions, after an overnight fastingof at least 10.00 hours, a high-fat (69 g fat; ˜65% fat), high-calorie(˜1,000 calories) breakfast with no EPA and DHA was provided to eachsubject exactly 30 minutes before their scheduled time of SC401administration. Subjects were required to consume the entire providedbreakfast within 30 minutes of it being served. Standard/controlledmeals with no EPA and DHA (˜22% fat) were provided at later times (seeabove).

Inclusion/Exclusion Criteria

Healthy male adult (aged 18 to 55 year, mean age 28 years) volunteerswith a body mass index (BMI) ranging between 18 kg/m² and 29.9 kg/m²(mean˜22 kg/m²) were recruited. At screening, eligible participants wereinstructed to avoid consumption of fish and fish oil for 3 weeks priorto the dosing. Enrolled subjects had no evidence of underlying disease,did not use any nicotine-containing products for at least 6 months priorto the study, did not have a history of HIV disease, had no evidence ofliver disease (cirrhosis, alcoholic liver disease, autoimmune hepatitisand chronic viral hepatitis), had no signs of Alzheimer's disease, didnot have a previous history of bile duct surgery, variceal hemorrhage,cholangiocarcinoma, or diabetes mellitus, had a fasting glucose level<126 mg/dL, and were not allergic to omega-3 fatty acids, ethyl esters,fish or shellfish.

Subjects were not eligible to participate in the study if they had amyocardial infarction, if they consumed >7 drinks per week, if they hada history of drug abuse within two years of screening, if they weretaking anti-thrombotic drugs, anti-psychotic medication, lipaseinhibitors, and unstable hormone replacement therapy medication, if theywere pregnant or lactating, or if they used warfarin.

Blood Collection and PK Data Analysis

Nineteen blood samples were collected at specified time points: −24,−12, −6, −1, and 0 hours before dosing and after administration at 0.25,0.50, 0.67, 0.83, 1, 1.33, 1.67, 2, 3, 4, 6, 8, 12 and 24 hours. Theconcentration of EPA and DHA total lipids and EPA and DHA FFA in plasmasamples were analyzed for those under fasting conditions. EPA and DHAtotal lipids, EPA and DHA FFA, and EPA and DHA EE in plasma wereanalyzed for subjects who were fed a high-fat, high-calorie meal. Allblood analyses were conducted using validated bioanalytical methods.

The following PK parameters for EPA and DHA plasma concentrations wereobtained from 30 subjects: Cmax, AUC_(0-t), AUC_(0-∞), Tmax, Kel, andt_(1/2). Baseline unadjusted and adjusted EPA and DHA total lipids, EPAand DHA FFA, and EPA and DHA EEs were calculated using thenon-compartmental model of WinNonlin® version 5.3 of PharsightCorporation, USA. The actual sampling times were used in the calculationof all PK measurements. All concentration values below the lower limitof quantification (LLOQ) were set to “zero” for all PK and statisticalcalculations. These plasma concentrations were further subjected tostatistical analysis using SAS® system for windows version 9.2 for thecalculation of descriptive statistics (arithmetic means, geometricmeans, standard deviations, coefficients of variation, minimums, mediansand maximums). Following the approach described by Davidson et al.(Davidson M H, Johnson Rooney M W, Kyle M L, Kling D F (2012) A novelomega-3 free fatty acid formulation has dramatically improvedbioavailability during a low-fat diet compared with omega-3 acid ethylesters: the ECLIPSE (EPANOVA® compared to LOVAZA® in a pharmacokineticsing-dose evaluation) study. J Clin Lipidol 6:573-584) baselineadjustments were calculated and presented herein for the PK parametersbecause the presence of endogenous levels of EPA and DHA may havecontributed to intra-subject variability and therefore may have affectedthe results and interpretation of the findings. The adjustments madewere for both each subject and specific time periods.

The baseline characteristics of the 60 male subjects enrolled in the fedand fasting bioavailability studies (n=30 each) are presented in Table21.

TABLE 21 Baseline characteristics of the study populations^(a) Fed Study(n = 30) Fasting Study (n = 30) Age (years) 28.0 ± 5.6 28.5 ± 6.8 Asianethnicity, 30 (100) 30 (100) n (%) Weight (kg) 63.7 ± 7.9 62.9 ± 7.9 BMI(kg/m²) 22.6 ± 2.4 22.0 ± 2.4 Blood pressure 117.7 ± 6.6  111.7 ± 4.5 systolic (mmHg) Blood pressure 77.5 ± 3.9 71.5 ± 4.3 diastolic (mmHg)Total cholesterol 165.9 ± 23.2 154.5 ± 31.8 (mg/dL) HDL-cholesterol 45.5± 7.4  45.9 ± 10.9 (mg/dL) LDL-cholesterol  99.8 ± 22.1  86.7 ± 27.2(mg/dL) Triglycerides 109.2 ± 62.7 109.3 ± 47.4 (mg/dL) Plasma glucose92.6 ± 7.5 87.0 ± 8.7 (mg/dL) Serum AST (U/L)  39.8 ± 17.0 26.7 ± 7.4Serum ALT (U/L)  48.2 ± 20.4  31.5 ± 14.1

The mean ages in the study populations were 28.0±5.6 (fed) and 28.5±6.8(fasting) years, respectively. All subjects were Asian with mean BMIs of22.6±2.4 (fed) and 22.0±2.4 (fasting), respectively. All blood lipidparameters were within normal limits. Both studies were completed by allenrolled subjects.

The administration of a single oral dose of SC401 was well tolerated inboth the fed and fasted state. No adverse events or serious adverseevents were reported and no safety concerns were raised during the twostudies.

The pharmacokinetic (PK) profiles and bioavailability of EPA and DHAcomprising the SC401 formulation is shown Tables 22-26 and graphicallyrepresented in FIGS. 5-9.

TABLE 22 Pharmacokinetic values for EPA and DHA total lipids after asingle dose of SC401B (2,172 mg of EPA + 996 mg of DHA) under fedconditions, N = 30 Parameter (Baseline-adjusted Arithmetic Coefficient90% Confidence Interval Geometric Change) Mean ± SD of Variation Limits(Lower, Upper) Mean EPA AUC_(0-t) (nmol · hr/mL)  2531.9 ± 1036.9 40.952221.0 2842.7 2136.3 C_(max) (nmol/mL)  312.9 ± 141.4 45.19 270.5 355.2267.4 Kel (1 hour) 0.0647 ± 0.020 31.12 0.058 0.070 0.062 T_(max) (hour) 5.87 ± 0.51 8.69 5.72 6.02 5.84 t½ (hour) 11.65 ± 3.57 30.65 10.5812.72 11.81 DHA AUC_(0-t) (nmol · hr/mL) 1008.2 ± 477.5 47.36 865.041151.4 892.8 C_(max) (nmol/mL) 146.89 ± 49.61 49.31 125.05 168.73 129.3Kel (1 hour) 0.0758 ± 0.032 43.39 0.066 0.085 0.0686 T_(max) (hour) 5.40 ± 0.93 17.26 5.12 5.67 5.31 t½ (hour) 11.36 ± 6.44 59.65 9.4313.29 10.10

TABLE 23 Pharmacokinetic parameters for EPA and DHA free fatty acids(FFA) after a single dose of SC401 (2,172 mg of EPA + 996 mg of DHA)under fed conditions, N = 30 Parameter (Baseline-adjusted ArithmeticCoefficient Geometric Change) Mean ± SD of Variation Median Mean EPAAUC_(0-t) (μg · h/mL) 10.82 ± 3.62  0.03 11.19 10.71 C_(max) (μg/mL)1.32 ± 0.51 0.04 1.39 1.27 T_(max) (hour) 5.52 ± 0.87 15.79 6.00 5.44 t½(hour) 14.85 ± 6.07  40.89 12.52 13.84 DHA AUC_(0-t) (μg · hr/mL) 4.91 ±3.80 0.77 4.45 4.13 C_(max) (μg/mL) 1.29 ± 0.65 0.05 1.23 1.30 T_(max)(hour) 5.86 ± 3.73 63.66 6.00 5.35 t½ (hour) 10.83 ± 6.06  55.97 12.228.78

TABLE 24 Pharmacokinetic parameters for EPA and DHA ethyl esters (EE)after a single dose of SC401 (2,172 mg of EPA + 996 mg of DHA) under fedconditions, N = 30 Parameter (Baseline-adjusted Arithmetic CoefficientGeometric Change) Mean ± SD of Variation Median Mean EPA AUC_(0-t) (μg ·h/mL) 0.40 ± 0.51 0.13 0.24 0.27 C_(max) (μg/mL) 0.18 ± 0.30 0.17 0.820.10 T_(max) (hour) 3.34 ± 1.59 47.61 3.00 2.99 t½ (hour) 3.63 ± 3.3491.88 2.35 2.54 DHA AUC_(0-t) (μg · hr/mL) 0.83 ± 0.65 0.08 0.64 0.65C_(max) (μg/mL) 0.31 ± 0.28 0.09 0.22 0.24 T_(max) (hour) 3.06 ± 0.7725.24 3.00 2.94 t½ (hour) 2.97 ± 4.48 150.81 1.54 1.83

TABLE 25 Pharmacokinetic parameters for EPA and DHA total lipids after asingle dose of SC401 (2,172 mg of EPA + 996 mg of DHA) under fastingconditions, N = 30 Parameter (Baseline-adjusted Arithmetic Coefficient90% Confidence Interval Geometric Change) Mean of Variation Limits(Lower, Upper) Mean EPA AUC_(0-t) (nmol · h/mL) 2203.60 ± 1034.9 46.961893.30 2513.93 2032.13 C_(max) (nmol/mL) 214.13 ± 98.67 46.07 184.55243.71 194.37 Kel (1 hour)  0.0718 ± 0.0246 34.22 0.0645 0.0791 0.0676T_(max) (hour)  5.23 ± 1.43 27.34 4.80 5.65 5.02 t½ (hour)  10.9 ± 4.2338.75 9.67 12.19 0.25 DHA AUC_(0-t) (nmol · h/mL) 1131.43 ± 484.3  42.80986.22 1276.64 1050.13 C_(max) (nmol/mL) 117.38 ± 51.66 51.66 101.90132.86 106.79 Kel (1 hour) 0.0800 ± 0.037 46.22 0.069 0.091 0.0719T_(max) (hour)  5.50 ± 1.48 26.90 5.056 5.94 5.29 t½ (hour) 11.09 ± 6.7761.04 9.061 13.11 9.63

TABLE 26 Pharmacokinetic parameters for EPA and DHA free fatty acids(FFA) after a single dose of SC401B (2,172 mg of EPA + 996 mg of DHA)under fasting conditions, N = 30 Parameter (Baseline-adjusted ArithmeticCoefficient Geometric Change) Mean ± SD of Variation Median Mean EPAAUC_(0-t) (μg · h/mL) 6.30 ± 2.01 0.03 6.389 5.96 C_(max) (μg/mL) 1.14 ±0.63 0.06 1.04 0.98 T_(max) (hour) 4.37 ± 0.85 19.47 4.00 4.30 t½ (hour)20.66 ± 22.79 110.28 12.72 13.31 DHA AUC_(0-t) (μg · hr/mL) 1.65 ± 1.790.11 1.37 1.34 C_(max) (μg/mL) 1.35 ± 0.82 0.61 1.33 1.26 T_(max) (hour)4.07 ± 0.38 9.45 4.00 4.06 t½ (hour) NC NC NC NC

Example 8 (Comparative)

This example compares the mean EPA and DHA total lipid plasmaconcentrations (base-line adjusted) after a singe dose of dose adjustedSC401, as manufactured according to Example 1, LOVAZA® and EPANOVA® inthe fed and fasted state over a 24 hr period. The LOVAZA® and EPANOVA®data were obtained from the ECLIPSE study conducted by Davidson et al.(Journal of Clinical Lipidology 2012 (6), 573-584). The SC401 data arederived from Example 7 above. The data are tabulated in Tables 27 and 28and graphically illustrated in FIGS. 10 and 11.

TABLE 27 Mean plasma concentration (μg/ml) of EPA and DHA total lipidsafter a single dose of dose adjusted SC401 vs LOVAZA ® vs EPANOVA ® infed conditions. Time (hrs) SC401 EPANOVA ® (low fat) LOVAZA ® 0 0.4 0 02 13.4 4.7 7.9 3 51.2 9.5 15.8 4 92.7 25.2 23.7 6 152 69 126 8 72.9 5473 10 55 54 63 12 40.2 50 59.9 14 35.8 47 57 16 31.6 44 55 18 29.4 41 5220 27 38 50 22 25 35 48 24 25 31.5 47

TABLE 28 Mean plasma concentration (μg/ml) of EPA and DHA total lipidsafter a single dose of dose adjusted SC401 vs LOVAZA ® in fastedconditions. Time (hrs) SC401 LOVAZA ® 0 0.2 0 2 12 4 3 59 4.2 4 80 5 6101 5.2 8 77 6 10 54 10 12 46 9 14 39 8 16 33 7.5 18 28.4 6.5 20 26 5.522 23 5 24 21 4

1. A pharmaceutical composition comprising EPA ethyl ester, DHA ethylester and at least one surface active agent, wherein said compositionwhen administered to a patient in need of treatment forhypertriglyceridemia, provides for a reduction of circulatingtriglyceride blood plasma levels of at least 25% greater than thereduction of circulating triglyceride blood plasma levels provided bythe administration of an Omega-3 fatty acid ethyl ester having anEPA:DHA ratio of about 1.3:1 at equivalent dosage strengths of EPA ethylester and DHA ethyl ester in said composition.
 2. The pharmaceuticalcomposition of claim 1, wherein said reduction of circulatingtriglyceride blood plasma levels is observed as early as 7 days afterthe initial administration.
 3. The pharmaceutical composition of claim1, wherein said reduction said reduction of circulating triglycerideblood plasma levels is observed 28 days after the initialadministration.
 4. The pharmaceutical composition of claim 1, whereinsaid patient in need of treatment has a mildly elevated base-line levelof circulating triglycerides (271-368 mg/dL).
 5. A pharmaceuticalcomposition comprising a mixture of EPA ethyl ester and DHA ethyl esterand at least one surface active agent; wherein said at least one surfaceactive agent comprises from about 0.5% (wt/wt) to about 5% (wt/wt) of ablock copolymer of polyethylene glycol and polypropylene glycolpoloxamer having a chemical formulaHO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H (Poloxamer 237); wherein thesurfactant HLB value is about 15 to about 17, wherein the composition isformulated in the form of a capsule, and wherein said composition isfree of omega-3 free fatty acids; and wherein said composition whenadministered to a patient in need of treatment for hypertriglyceridemia,provides for a reduction of circulating triglyceride blood plasma levelsof at least 25% greater than the reduction of circulating triglycerideblood plasma levels provided by the administration of an Omega-3 fattyacid ethyl ester having an EPA:DHA ratio of about 1.3:1 at equivalentdosage strengths of EPA ethyl ester and DHA ethyl ester in saidcomposition.
 6. The pharmaceutical composition of claim 5, wherein saidreduction of circulating triglyceride blood plasma levels is observed asearly as 7 days after the initial administration.
 7. The pharmaceuticalcomposition of claim 5, wherein said reduction said reduction ofcirculating triglyceride blood plasma levels is observed 28 days afterthe initial administration.
 8. The pharmaceutical composition of claim5, wherein said patient in need of treatment has a mildly elevatedbase-line level of circulating triglycerides (271-368 mg/dL).
 9. Thepharmaceutical composition of claim 5, wherein the compositionself-micellizes in an aqueous medium.
 10. The pharmaceutical compositionof claim 9, wherein the micelles have an average diameter of from about1 μm to about 10 μm.
 11. The pharmaceutical composition of claim 10,wherein the micelles are stable for at least 12 months at ambienttemperature.
 12. A micelle dosage form composition comprising pre-formedmicelles in an aqueous medium, wherein said dosage form composition isprepared by adding the composition of claim 9 to an aqueous medium. 13.The composition of claim 12, wherein said adding is without anyagitation.
 14. The pharmaceutical composition of claim 5, furthercomprising polysorbate 80 present between about 20% (wt/wt) to about 31%(wt/wt) of said composition.
 15. The pharmaceutical composition of claim5, further comprising the ingredient pure d-limonene.
 16. Apharmaceutical composition comprising EPA ethyl ester and DHA ethylester and at least one surface active agent, wherein when administeredto a patient in need of treatment for hypertriglyceridemia, provides anincrease of at least 1.5 fold of the circulating blood plasma levels ofEPA and DHA total lipids compared to the respective circulating bloodplasma levels of EPA and DHA total lipids provided by the administrationof an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio of about1.3:1® or a combination of EPA and DHA in free acid form at equivalentdosage strengths of EPA ethyl ester and DHA ethyl ester in saidcomposition under a fed state.
 17. The pharmaceutical composition ofclaim 16, wherein said increase of circulating EPA and DHA total lipidlevels in the blood plasma levels is observed as early as 7 days afterthe initial administration.
 18. The pharmaceutical composition of claim16, wherein said increase of circulating EPA and DHA total lipid levelsin the blood plasma levels is observed 28 days after the initialadministration.
 19. The pharmaceutical composition of claim 16, whereinsaid patient in need of treatment has a mildly elevated base-line levelof circulating triglycerides (271-368 mg/d L).
 20. A pharmaceuticalcomposition comprising a mixture of EPA ethyl ester and DHA ethyl esterand at least one surface active agent; wherein said at least one surfaceactive agent comprises from about 0.5% (wt/wt) to about 5% (wt/wt) of ablock copolymer of polyethylene glycol and polypropylene glycolpoloxamer having a chemical formulaHO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H (Poloxamer 237); wherein thesurfactant HLB value is about 15 to about 17, wherein the composition isformulated in the form of a capsule, and wherein said composition isfree of omega-3 free fatty acids; and wherein said composition whenadministered to a patient in need of treatment for hypertriglyceridemia,provides an increase of at least 1.5 fold of the circulating bloodplasma levels of EPA and DHA total lipids compared to the respectivecirculating blood plasma levels of EPA and DHA total lipids provided bythe administration of an Omega-3 fatty acid ethyl ester having anEPA:DHA ratio of about 1.3:1 or a combination of EPA and DHA in freeacid form at equivalent dosage strengths of EPA ethyl ester and DHAethyl ester in said composition under a fed state.
 21. Thepharmaceutical composition of claim 20, wherein said increase incirculating EPA and DHA total lipids in blood plasma levels is observedas early as 7 days after the initial administration.
 22. Thepharmaceutical composition of claim 20, wherein said increase incirculating EPA and DHA total lipids in blood plasma levels is observed28 days after the initial administration.
 23. The pharmaceuticalcomposition of claim 20, wherein said patient in need of treatment has amildly elevated base-line level of circulating triglycerides (271-368mg/d L).
 24. The pharmaceutical composition of claim 20, wherein thecomposition self-micellizes in an aqueous medium.
 25. The pharmaceuticalcomposition of claim 24, wherein the micelles have an average diameterof from about 1 μm to about 10 μm.
 26. The pharmaceutical composition ofclaim 25, wherein the micelles are stable for at least 12 months atambient temperature.
 27. A micelle dosage form composition comprisingpre-formed micelles in an aqueous medium, wherein said dosage formcomposition is prepared by adding the composition of claim 24 to anaqueous medium.
 28. The composition of claim 27, wherein said adding iswithout any agitation.
 29. The pharmaceutical composition of claim 20,further comprising polysorbate 80 present between about 20% (wt/wt) toabout 31% (wt/wt) of said composition.
 30. The pharmaceuticalcomposition of claim 20, further comprising the ingredient pured-limonene.
 31. A pharmaceutical composition comprising EPA ethyl esterand DHA ethyl ester and at least one surface active agent, wherein whenadministered to a patient in need of treatment for hypertriglyceridemia,provides an increase of at least 10-fold of the circulating blood plasmalevels of EPA and DHA total lipids compared to the respectivecirculating blood plasma levels of EPA and DHA total lipids provided bythe administration of an Omega-3 fatty acid ethyl ester having anEPA:DHA ratio of about 1.3:1 at equivalent dosage strengths of EPA ethylester and DHA ethyl ester under a fasted state.
 32. The pharmaceuticalcomposition of claim 31, wherein said increase in circulating EPA andDHA total lipids in blood plasma levels is observed as early as 7 daysafter the initial administration.
 33. The pharmaceutical composition ofclaim 31, wherein said increase in circulating EPA and DHA total lipidsin blood plasma levels is observed 28 days after the initialadministration.
 34. The pharmaceutical composition of claim 31, whereinsaid patient in need of treatment has a mildly elevated base-line levelof circulating triglycerides (271-368 mg/d L).
 35. A pharmaceuticalcomposition comprising a mixture of EPA ethyl ester and DHA ethyl esterand at least one surface active agent; wherein said at least one surfaceactive agent comprises from about 0.5% (wt/wt) to about 5% (wt/wt) of ablock copolymer of polyethylene glycol and polypropylene glycolpoloxamer having a chemical formulaHO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H (Poloxamer 237); wherein thesurfactant HLB value is about 15 to about 17, wherein the composition isformulated in the form of a capsule, and wherein said composition isfree of omega-3 free fatty acids; and wherein said composition whenadministered to a patient in need of treatment for hypertriglyceridemia,provides an increase of at least 10-fold of the circulating blood plasmalevels of EPA and DHA total lipids compared to the respectivecirculating blood plasma levels of EPA and DHA total lipids provided bythe administration of an Omega-3 fatty acid ethyl ester having anEPA:DHA ratio of about 1.3:1 at equivalent dosage strengths of EPA ethylester and DHA ethyl ester under a fasted state.
 36. The pharmaceuticalcomposition of claim 35, wherein said increase in circulating EPA andDHA total lipids in blood plasma levels is observed as early as 7 daysafter the initial administration.
 37. The pharmaceutical composition ofclaim 35, wherein said increase in circulating EPA and DHA total lipidsin blood plasma levels is observed 28 days after the initialadministration.
 38. The pharmaceutical composition of claim 35, whereinsaid patient in need of treatment has a mildly elevated base-line levelof circulating triglycerides (271-368 mg/d L).
 39. The pharmaceuticalcomposition of claim 35, wherein the composition self-micellizes in anaqueous medium.
 40. The pharmaceutical composition of claim 39, whereinthe micelles have an average diameter of from about 1 μm to about 10 μm.41. The pharmaceutical composition of claim 40, wherein the micelles arestable for at least 12 months at ambient temperature.
 42. A micelledosage form composition comprising pre-formed micelles in an aqueousmedium, wherein said dosage form composition is prepared by adding thecomposition of claim 39 to an aqueous medium.
 43. The composition ofclaim 42, wherein said adding is without any agitation.
 44. Thepharmaceutical composition of claim 35, further comprising polysorbate80 present between about 20% (wt/wt) to about 31% (wt/wt) of saidcomposition.
 45. The pharmaceutical composition of claim 35, furthercomprising the ingredient pure d-limonene.
 46. A pharmaceuticalcomposition of claim 1 wherein said composition does not contain atleast one selected from the group consisting of palmitic acid, linoleicacid, oleic acid either individually or in combination.
 47. Apharmaceutical composition comprising EPA ethyl ester, DHA ethyl esterand at least one surface active agent, when administered to a patient inneed of treatment for hypertriglyceridemia, wherein the C_(max) of totalEPA and DHA total lipid plasma concentration provided by saidcomposition is at least about 1.5 times greater than the C_(max) oftotal EPA and DHA total lipid plasma concentration provided by an equaldosage of an Omega-3 fatty acid ethyl ester having an EPA:DHA ratio ofabout 1.3:1 or a combination of EPA and DHA in free acid form whenadministered under fed conditions.
 48. The pharmaceutical composition ofclaim 47, wherein said reduction of circulating triglyceride bloodplasma levels is observed as early as 7 days after the initialadministration.
 49. The pharmaceutical composition of claim 47, whereinsaid reduction said reduction of circulating triglyceride blood plasmalevels is observed 28 days after the initial administration.
 50. Thepharmaceutical composition of claim 47, wherein said patient in need oftreatment has a mildly elevated base-line level of circulatingtriglycerides (271-368 mg/d L).
 51. A pharmaceutical compositioncomprising EPA ethyl ester, DHA ethyl ester and at least one surfaceactive agent, when administered to a patient in need of treatment forhypertriglyceridemia, wherein the C_(max) of total EPA and DHA totallipid plasma concentration provided by said composition is at leastabout 1.5 times greater than the C_(max) of total EPA and DHA totallipid plasma concentration provided by an equivalent dosage of anOmega-3 fatty acid ethyl ester having an EPA:DHA ratio of about 1.3:1 ora combination of EPA and DHA in free acid form when administered underfed conditions.
 52. A pharmaceutical composition comprising EPA ethylester, DHA ethyl ester and at least one surface active agent, whenadministered to a patient in need of treatment for hypertriglyceridemia,provide for a C_(max) of total EPA and DHA total lipid plasmaconcentration that is at least about 10-fold greater than the C_(max) oftotal EPA and DHA total lipid plasma concentration provided by anequivalent dosage of an Omega-3 fatty acid ethyl ester having an EPA:DHAratio of about 1.3:1 when administered under fasted conditions.
 53. Apharmaceutical composition comprising a mixture of EPA ethyl ester andDHA ethyl ester and at least one surface active agent; wherein said atleast one surface active agent comprises from about 0.5% (wt/wt) toabout 5% (wt/wt) of a block copolymer of polyethylene glycol andpolypropylene glycol poloxamer having a chemical formulaHO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H (Poloxamer 237); wherein thesurfactant HLB value is about 15 to about 17, wherein the composition isformulated in the form of a capsule, and wherein said composition isfree of omega-3 free fatty acids; and wherein said composition whenadministered to a patient in need of treatment for hypertriglyceridemia,provide for a C_(max) of total EPA and DHA total lipid plasmaconcentration that is at least about 10-fold greater than the C_(max) oftotal EPA and DHA total lipid plasma concentration provided by anequivalent dosage of an Omega-3 fatty acid ethyl ester having an EPA:DHAratio of about 1.3:1 when administered under fasted conditions.
 54. Apharmaceutical composition comprising a mixture of EPA ethyl ester andDHA ethyl ester and at least one surface active agent; wherein said atleast one surface active agent comprises from about 0.5% (wt/wt) toabout 5% (wt/wt) of a block copolymer of polyethylene glycol andpolypropylene glycol poloxamer having a chemical formulaHO(C₂H₄O)₆₄(C₃H₆O)₃₇(C₂H₆O)₃₇(C₂H₄O)₆₄H (Poloxamer 237); wherein thesurfactant HLB value is about 15 to about 17, wherein the composition isformulated in the form of a capsule, and wherein said composition isfree of omega-3 free fatty acids; and wherein said composition whenadministered to a patient in need of treatment for hypertriglyceridemia,provide for a C_(max) of total EPA and DHA total lipid plasmaconcentration that is at least about 1.5-fold greater than the C_(max)of total EPA and DHA total lipid plasma concentration provided by anequivalent dosage of an Omega-3 fatty acid ethyl ester having an EPA:DHAratio of about 1.3:1 or a combination of EPA and DHA in free acid formwhen administered under fed conditions.